Pyridazino-pyridinone Compounds and Methods of Use

ABSTRACT

The present invention comprises a new class of compounds useful for the prophylaxis and treatment of protein kinase mediated diseases, including inflammation and related conditions. The compounds have a general Formula I 
     
       
         
         
             
             
         
       
     
     wherein A, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X and n are defined herein. The invention also comprises pharmaceutical compositions including one or more compounds of Formula I, uses of such compounds and compositions for treatment of p38 map kinase mediated diseases including rheumatoid arthritis, psoriasis, chronic obstructive pulmonary disease, pain and other inflammatory disorders, as well as intermediates and processes useful for the preparation of compounds of Formula I.

RELATED APPLICATIONS

This application is the U.S. national filing, under 35 U.S.C. §371, ofInternational Application No. PCT/US2009/055093, filed Aug. 26, 2009,which application in turn claims the benefit of U.S. Provisional PatentApplication Nos. 61/092,930 and 61/146,139, filed on Aug. 29, 2008 andJan. 21, 2009, respectively, all specifications of which are both herebyincorporated herein by reference in their entireties.

FIELD OF THE INVENTION

The invention relates generally to the field of pharmaceutical agentsand, more specifically, to pharmaceutically active compounds,pharmaceutical compositions and methods of use thereof, to treat variousdisorders, including TNF-α, IL-1β, IL-6 and/or IL-8 mediated diseasesand other maladies, such as inflammation and pain. The invention alsorelates to intermediates and processes useful in the preparation of suchcompounds.

BACKGROUND OF THE INVENTION

Protein kinases represent a large family of enzymes, which catalyze thephosphorylation of target protein substrates. The phosphorylation is atransfer reaction of a phosphate group from ATP to the proteinsubstrate. Common points of attachment for the phosphate group to theprotein substrate include, for example, a tyrosine, serine or threonineresidue. Protein tyrosine kinases (PTKs) are enzymes, which catalyze thephosphorylation of specific tyrosine residues in cellular proteins.Examples of kinases in the protein kinase family include, withoutlimitation, abl, Akt, bcr-abl, Blk, Brk, Btk, c-kit, c-Met, c-src,c-fms, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10,cRaf1, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, Erk, Fak, fes, FGFR1,FGFR2, FGFR3, FGFR4, FGFR5, Fgr, flt-1, Fps, Frk, Fyn, Hck, IGF-1R,INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, ros, tie,tie2, TRK, Yes, and Zap70. Due to their activity in numerous cellularprocesses, protein kinases have emerged as important therapeutictargets.

Protein kinases play a central role in the regulation and maintenance ofa wide variety of cellular processes and cellular function. For example,kinase activity acts as molecular switches regulating inflammatorycytokine production via various pathways. Uncontrolled or excessivecytokine production has been observed in many disease states, andparticularly in those related to inflammation.

The p38 protein kinase has been reported to be involved in theregulation of inflammatory cytokines. Interleukin-1 (IL-1) and TumorNecrosis Factor α (also referred to herein as TNF-α or TNF) arepro-inflammatory cytokines secreted by a variety of cells, includingmonocytes and macrophages, in response to many inflammatory stimuli(e.g., lipopolysaccharide (LPS)) or external cellular stress (e.g.,osmotic shock and peroxide).

Elevated levels of TNF-α over basal levels have been implicated inmediating or exacerbating a number of disease states includingrheumatoid arthritis (RA); osteoarthritis; rheumatoid spondylitis; goutyarthritis; inflammatory bowel disease (IBD); adult respiratory distresssyndrome (ARDS); psoriasis; Crohn's disease; allergic rhinitis;ulcerative colitis; anaphylaxis; contact dermatitis; asthma; muscledegeneration; cachexia; Reiter's syndrome; type II diabetes; boneresorption diseases; graft vs. host reaction; ischemia reperfusioninjury; atherosclerosis; brain trauma; multiple sclerosis; cerebralmalaria; sepsis; septic shock; toxic shock syndrome; fever, and myalgiasdue to infection. HIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), influenza,adenovirus, the herpes viruses (including HSV-1, HSV-2), and herpeszoster are also exacerbated by TNF-α.

TNF-α has been reported to play a role in head trauma, stroke, andischemia. For instance, in animal models of head trauma (rat), TNF-αlevels increased in the contused hemisphere (Shohami et al., J. Cereb.Blood Flow Metab. 14:615 (1994)). In a rat model of ischemia wherein themiddle cerebral artery was occluded, the levels of TNF-α mRNA of TNF-αincreased (Feurstein et al., Neurosci. Lett., 164:125 (1993)).Administration of TNF-α into the rat cortex has been reported to resultin significant neutrophil accumulation in capillaries and adherence insmall blood vessels. TNF-α promotes the infiltration of other cytokines(IL-1β, IL-6) and also chemokines, which promote neutrophil infiltrationinto the infarct area (Feurstein, Stroke 25:1481 (1994)).

TNF-α appears to play a role in promoting certain viral life cycles anddisease states associated therewith. For instance, TNF-α secreted bymonocytes induced elevated levels of HIV expression in a chronicallyinfected T cell clone (Clouse et al., J. Immunol. 142:431 (1989)).Landevirta et al., (Am. J. Med. 85:289 (1988)) discussed the role ofTNF-α in the HIV associated states of cachexia and muscle degradation.

TNF-α is upstream in the cytokine cascade of inflammation. As a result,elevated levels of TNF-α may lead to elevated levels of otherinflammatory and proinflammatory cytokines, such as IL-1, IL-6, andIL-8. Elevated levels of IL-1 over basal levels have been implicated inmediating or exacerbating a number of disease states includingrheumatoid arthritis; osteoarthritis; rheumatoid spondylitis; goutyarthritis; inflammatory bowel disease; adult respiratory distresssyndrome (ARDS); psoriasis; Crohn's disease; ulcerative colitis;anaphylaxis; muscle degeneration; cachexia; Reiter's syndrome; type IIdiabetes; bone resorption diseases; ischemia reperfusion injury;atherosclerosis; brain trauma; multiple sclerosis; sepsis; septic shock;and toxic shock syndrome. Viruses sensitive to TNF-α inhibition, e.g.,HIV-1, HIV-2, HIV-3, are also affected by IL-1.

Antagonism of TNF-α has been reported to be beneficial for treatinguveitis (Reiff et al, A&R 44:141-145 (2001)); Sepsis (Abraham, Lancet,351:929 (1998)); Systemic Lupus Erythrematosis (SLE) (Aringer, A&R,50:3161 (2004)); Graft vs Host Disease (Couriel, Curr. Opinion Oncology,12:582 (2000)); Polymyositis and Dermatomyositis (Labiache,Rheumatology, 43:531 (2004)); Type II diabetes (Ruan, Cytokine GFReview, 14:447 (2003)); Sjogren's disease (Marriette, A&R, 50:1270(2004)), Sarcoidosis (Roberts, Chest, 124:2028 (2003)); Wegener'sgranulomatosis (WGET, New England J. Med., 352:351 (2005)) and post MIcardiac dysfunction (Sugano et al, Mol. Cell. Bioch., 266:127 (2004)).In addition, TNF-α has been reported to play a role in SAPHO, periodicfever, relapsing polychrondritis, multicentric reticulohistiocytosis,macrophage activation syndrome, Hyper IgD syndrome, familial Hibernianfever, Pyoderma gangrenosum, Cochleovestibular disorders, Cicatricalpemphigoid, Herniated intervertebral disc diseases, amyloidosis, CINCAsyndrome, myelodisplastic syndrome, alcoholic hepatitis, andendometriosis. Finally, indications which have already been approved fortreatment with a therapeutic agent which modulates TNF-α levels in theplasma, and/or other pro-inflammatory cytokines, include withoutlimitation, inflammatory bowel disease (IBD), psoriatis arthritis,ankylosing spondylitis and juvenile RA.

TNF-α and IL-1 appear to play a role in pancreatic β cell destructionand diabetes. Pancreatic β cells produce insulin which helps mediateblood glucose homeostasis. Deterioration of pancreatic β cells oftenaccompanies type I diabetes. Pancreatic β cell functional abnormalitiesmay occur in patients with type II diabetes. Type II diabetes ischaracterized by a functional resistance to insulin. Further, type IIdiabetes is also often accompanied by elevated levels of plasma glucagonand increased rates of hepatic glucose production. Glucagon is aregulatory hormone that attenuates liver gluconeogenesis inhibition byinsulin. Glucagon receptors have been found in the liver, kidney andadipose tissue. Thus, glucagon antagonists are useful for attenuatingplasma glucose levels (WO 97/16442, incorporated herein by reference inits entirety). By antagonizing the glucagon receptors, it is thoughtthat insulin responsiveness in the liver will improve, therebydecreasing gluconeogenesis and lowering the rate of hepatic glucoseproduction. Elevation of glucose levels along with the reducedexpression of IL-1Ra, an antagonist of IL-1 signaling, leads to impairedinsulin secretion, decreased cell proliferation and apoptosis Inhibitonof IL-1 action has been shown to improve glycemia, b-cell secretoryfunction and reduce markers of systemic inflammation (Larsen, NewEngland J. Med., 356: 1517 (2007).

In rheumatoid arthritis models in animals, multiple intra-articularinjections of IL-1 led to an acute and destructive form of arthritis(Chandrasekhar et al., Clinical Immunol Immunopathol., 55:382 (1990)).In studies using cultured rheumatoid synovial cells, IL-1 is a morepotent inducer of stromelysin than is TNF-α (Firestein, Am. J. Pathol.,140:1309 (1992)). At sites of local injection, neutrophil, lymphocyte,and monocyte emigration has been observed. The emigration is attributedto the induction of chemokines (e.g., IL-8), and the up-regulation ofadhesion molecules (Dinarello, Eur. Cytokine Netw., 5:517-531 (1994)).

IL-1 also appears to play a role in promoting certain viral life cycles.For example, cytokine-induced increase of HIV expression in achronically infected macrophage line has been associated with aconcomitant and selective increase in IL-1 production (Folks et al., J.Immunol., 136:40 (1986)). Beutler et al. (J. Immunol., 135:3969 (1985))discussed the role of IL-1 in cachexia. Baracos et al. (New Eng. J.Med., 308:553 (1983)) discussed the role of IL-1 in muscle degeneration.

In rheumatoid arthritis (RA), both IL-1 and TNF-α induce synoviocytesand chondrocytes to produce collagenase and neutral proteases, whichleads to tissue destruction within the arthritic joints. In an in-vivoanimal model of arthritis, i.e., collagen-induced arthritis (CIA) inrats and mice, intra-articular administration of TNF-α either prior toor after the induction of CIA led to an accelerated onset of arthritisand a more severe course of the disease (Brahn et al., LymphokineCytokine Res. 11:253 (1992); and Cooper, Clin. Exp. Immunol., 898:244(1992)). IL-1 and TNF-α have been implicated in pro-inflammatorymechanisms in many human diseases including inflammatory arthritis,inflammatory bowel disease sepsis syndrome and both acute and cheonisinflammation of many organs. (Vassali P., The Pathophysiology of TumorNecrosis Factors, Ann. Rev. Immunology 10: 411-452 (1992) and DinarelloC A, Biologic Basis for Interluekin-1 in disease, Blood, 87:2095-2147(1996)).

IL-6 also appears to play a role in, and therefore have applications to,pro-inflammatory and other malignant diseases. Particularly, deregulatedlevels of IL-6 are associated with various immunological diseases, suchas RA, systemic juvenile idiopathic arthritis (sJIA), polyarticular typeJIA, systemic lupus erythematosus (SLE), vasculitis syndrome, CastlemanDisease and Crohn's Disease; transplantation conditions such as acuterejection and graft-versus-host disease (GVHD); respiratory diseasessuch as interstitial pneumonia and bronchial; asthma; bone diseases suchas osteoporosis and Paget's disease, as well as various malignantdisease including multiple myeloma, renal cancer, prostate cancer,cardiac mixoma, Kaposis sarcoma, Mesothelioma, Malignant lymphoma, lungcancer and gastric cancer. (Nishimoto and Kishimoto, Review, 2: 619-625(2006)). It follows that the reduction and/or regulation of IL-6 levelsmay be useful for treatment of one or more of the above diseases.

IL-8 has been implicated in exacerbating and/or causing many diseasestates in which massive neutrophil infiltration into sites ofinflammation or injury (e.g., ischemia) is mediated by the chemotacticnature of IL-8, including, but not limited to, the following: asthma,inflammatory bowel disease, psoriasis, adult respiratory distresssyndrome, cardiac and renal reperfusion injury, thrombosis andglomerulonephritis. In addition to the chemotaxis effect on neutrophils,IL-8 also has the ability to activate neutrophils. Thus, reduction inIL-8 levels may lead to diminished neutrophil infiltration.

The role and activity of the p38 protein in RA and otherpro-inflammatory cytokine mediated diseases and conditions are becomingbetter understood. For example, Korb et al., Arthritis and Rheumatism,54: 2745-2756 (2006) describes the activation of the p38 alpha (p38α)and p38 gamma (p38γ) and the role which these two isoforms play in thedevelopment and progression of RA. Korb further describes thecorrelation between expression of p38 and the incidence of CRP in RA.Korb has found that the expression of these isoforms dominate inpatients with chronic inflammation and, therefore, concludes thateffective strategies to inhibit p38 kinase should aim to specificallytarget either or both of the isoforms. Medicherla et al., J.Pharmacology and Experimental Therapeutics, 318, 132-141 (2006) andNishikawa et al., Arthritis & Rheumatism, 48, 2670-2681 (2003) describeresults of an in-vivo collegan-induced arthritis (CIA) model in the ratand mouse. More specifically, they report that, in both animals,inhibition of p38α activity and related signaling improved clinicalscore and reversed bone and cartilage destruction. Ferrari,Cardiovascular Research 37:554 (1998) and Jacobsson et al., J Rheum.32:1213 (2005) describe how pro-inflammatory cytokines, such as TNF andIL-1, play a role in cadiovascular disease. More specifically, they havefound that blocking or reducing the levels of TNF-α have a protectiveeffect, and reduce the incidence of cardiovascular disease in RApatients. Behr et al., Circulation, 104, 1292 (2001) describes theability and efficacy of a p38 kinase inhibitor in treating hypertensivecardiac hypertrophy.

Proof of biological connection between the role and function of p38α mapkinase pro-inflammatory cytokine production is very clear. Though p38αnull mice are not viable, embryonic stem cells taken from these miceshow a reduced capacity for IL-1 induced production and activation ofMAP kinase-activated protein kinase-2 (MAPKAP-2), a downstream substrateof p38α map kinase in response to stress (J. Exp. Med. 191, 859-869,2000). More importantly, MAPKAP-2 deficient mice also show diminishedproduction of IL-6 and TNF ((Kotlyarov, A. et al, “MAPKAP kinase 2 isEssential for LPS-induced TNF-α Biosynthesis”, Nature Cell Biology, 1,94-97, 1999). So p38α/MAPKAP pathway is crutial to inflammatory cytokineproduction and signaling. Furthermore, p38α phosphorylates a variety oftranscriptional factors, some of which are responsible for transcriptionexpression of genes encoding inflammatory cytokines (Kumar, S. et al,“p38 MAP kinases: key signaling molecules as Therapeutic targets forInflammatory Disease”, Nature Review Drug Discovery, 2, 717-726, 2003).

Rheumatoid arthritis (RA) is a common inflammatory disease of synovialjoints and is characterized by the production of pro-inflammatorycytokines/mediators by immune cells that infiltrate synovium. Thiscauses proliferation of synovial fibroblasts, further release cytokineinflammatory molecules and formation of pannus tissue that eventuallydegrades cartilage and subchondral bone, leading to joint destruction,pain and disability. IL-1 and TNF are the two most importantinflammatory cytokines in stimulating the destructive cascade ofinflammation pathway, the production of secondary mediators, such asprostaglandins E2 (PGE2) matrix metalloprteinases and vascular celladhesion molecules and others. Agents that restrict the availability ofTNF or IL-1 have been shown to be efficacious in animal models and inthe clinic for RA and Crohn's Disease.

There have been commercial successes targeting reduction of TNF. Theanti-TNF antibody infliximab (Remicade, Centicore) and the TNFreceptor-Fc fusion protein Etanercept (Enbrel; Amgen) bind to TNF andprevent it from binding to cell surface receptors, thereby inhibitingits biological actions Anakinra (Kineret; Amgen), a soluble IL-1receptor antagonist has been approved for the treatment of RA by the USregulatory authority (Food and Drug Administration or FDA). Enbrel hasbeen approved by the US FDA for moderate to severe RA, juvenile RA,ankylosing spondylitis, plaque psoriasis, and psoriatic arthritis.Adalimumab (Humira), which binds to TNFα and prevents activation of theTNF receptor, has also been approved for commercial use for similarindications.

In addition, there are a number of small molecule p38 inhibitors whichhave been approved by the FDA, based on safety and efficacy data inanimal models, for clinical trials in humans. These agents areundergoing safety and therapeutic efficacy trials, notably for RA, butalso for other TNF related conditions, including, without limitation,Crohn's, MS, psoriasis, related dermatitis, and other indications whichhave been approved or are clearly connected with pro-inflammatorycytokines such as TNF and IL-1. Other TNF related indications arearising as well. For instance, Array 797, a small molecule p38inhibitor, is in phase II trials for treating pain in dental patients.

Consequently, many approaches to treating pro-cytokine mediatedinflammatory diseases and conditions have been conducted. For example,small molecule SB-203580a traryl imidazole, was developed as apharmacological tool to show a correlation between the binding of thecompound inside the cell to inhibit the natural function of p38α and theinhibition of cell cytokine synthesis (Nature 372, 739-746, 1994).

Several approaches have been taken to block the effect of TNF-α. Oneapproach involves using soluble receptors for TNF-α (e.g., TNFR-55 orTNFR-75), which have demonstrated efficacy in animal models ofTNF-α-mediated disease states. A second approach to neutralizing TNF-αusing a monoclonal antibody specific to TNF-α, cA2, has demonstratedimprovement in swollen joint count in a Phase II human trial ofrheumatoid arthritis (Feldmann et al., Immunological Reviews, pp.195-223 (1995)). These approaches block the effects of TNF-α and IL-1 byeither protein sequestration or receptor antagonism.

Yet another approach to block the effect of TNF-α, and otherpro-inflammatory cytokines, has been to modulate the activity of the p38kinase enzyme. For example, the PCT publication, WO 04/010995, publishedon Feb. 5, 2004, describes fused heteroaryl derivatives for use as p38kinase inhibitors in the treatment of I.A. and rheumatoid arthritis; PCTpublication, WO 2005/009937, published on Feb. 3, 2005, describes5-membered heterocycle-based p38 kinase inhibitors; U.S. Pat. No.6,635,644, issued Oct. 21, 2003, describes fused nitrogen-containingbicyclic ring systems as p38 inhibitors; and U.S. Pat. No. 6,794,380,issued Sep. 21, 2004, describes amide derivatives as p38 inhibitors.Despite the ongoing efforts, there needs to be effectiveanti-inflammatory agents which regulate the production ofpro-inflammatory cytokines, including TNF-α, IL-1β, IL-6 and/or IL-8, totreat related diseases and conditions.

BRIEF DESCRIPTION OF THE INVENTION

The present invention provides a new class of compounds useful in theprophylaxis and treatment of diseases mediated by pro-inflammatorycytokines, such as TNF-α, IL-1β, IL-6 and/or IL-8. The compounds,including stereoisomers, tautomers, solvates, pharmaceuticallyacceptable salts, derivatives or prodrugs thereof, are generally definedby Formula I

wherein A, R¹, R², R³, R⁴, R⁵, R⁶, X and n are as described below. Theinvention also provides procedures for making compounds of Formula I,compounds of Formula II, and intermediates useful in such procedures.

The compounds provided by the invention are capable of modulating thep38 kinase protein. To this end, the compounds of the invention areuseful for regulating the levels of pro-inflammatory cyclokines and fortherapeutic, prophylactic, acute and/or chronic treatment of TNF-α,IL-1β, IL-6 and/or IL-8 mediated diseases, such as those describedherein. For example, the compounds are useful for the prophylaxis andtreatment of RA, pain, and other conditions involving inflammation. Inanother embodiment, the invention provides pharmaceutical compositions,also commonly referred to as “medicaments”, comprising one or more ofthe compounds of the invention in combination with one or morepharmaceutically acceptable carrier(s) or excipient(s). Suchpharmaceutical compositions are useful to attenuate, alleviate, or treatp38 kinase-mediated disorders through inhibition of the activity of thep38 kinase enzyme.

The foregoing merely summarizes certain aspects of the invention and isnot intended, nor should it be construed, as limiting the invention inany way. All patents and other publications recited herein are herebyincorporated by reference in their entirety.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment of the invention, the compounds, includingstereoisomers, tautomers, solvates, pharmaceutically acceptable salts,derivatives or prodrugs thereof, are defined by general Formula I:

wherein

A is CR⁵ or N;

R¹ is C₁₋₈-alkyl, —OC₁₋₈-alkyl, —SC₁₋₈-alkyl, —NHC₁₋₈-alkyl,—N(C₁₋₈-alkyl)₂, C₂₋₈-alkenyl, C₂₋₈-alkynyl or C₃₋₈-cycloalkyl, each ofwhich is optionally substituted with 1-5 substituents of R⁹,

or R¹ is a 3-8 membered monocyclic or 6-12 membered bicyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, saidheteroatoms selected from O, N, or S, wherein said ring system isoptionally substituted independently with 1-5 substituents of R⁹;

each of R² and R³, independently, is H, halo, haloalkyl, NO₂, CN,C₁₋₆-alkyl, C₁₋₆-alkoxyl, C₁₋₆-thioalkyl, C₁₋₆-aminoalkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl or C₃₋₆-cycloalkyl, each of the C₁₋₆-alkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl and C₃₋₁₀-cycloalkyl optionally substituted with 1-5substituents of R⁹;

R⁴ is CN, C(O)R⁹, C₁₋₆-alkyl, —OC₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynylor C₃₋₆-cycloalkyl, each of the C₁₋₆-alkyl, —OC₁₋₆-alkyl, C₂₋₆-alkenyl,C₂₋₁₀-alkynyl and C₃₋₆-cycloalkyl optionally substituted with 1-5substituents of R⁹;

each R⁵, independently, is H, halo, haloalkyl, NO₂, CN, OH, C₁₋₆-alkyl,—OC₁₋₆-alkyl, —SC₁₋₆-alkyl, —NHC₁₋₆-alkyl, wherein the C₁₋₆-alkyl ofeach is optionally comprising 1-3 heteroatoms selected from N, O and Sand optionally substituted with 1-5 substituents of R⁹;

R⁶ is C(O)NR⁷R⁷, C(O)NR⁷R⁸, NR⁷C(O)R⁷, NR⁷C(O)R⁸, NR⁷C(O)NR⁷R⁷,NR⁷C(O)NR⁷R⁸, S(O)₂NR⁷R⁷, S(O)₂NR⁷R⁸, NR⁷S(O)₂NR⁷R⁸, NR⁷S(O)₂R⁷ orNR⁷S(O)₂R⁸;

each R⁷, independently, is H, C₁₋₈-alkyl, C₂₋₈-alkenyl, C₂₋₈-alkynyl orC₃₋₈-cycloalkyl, each of the C₁₋₈-alkyl, C₂₋₈-alkenyl, C₂₋₈-alkynyl andC₃-cycloalkyl optionally comprising 1-4 heteroatoms selected from N, Oand S and optionally substituted with one or more substituents of NR⁸R⁹,NR⁹R⁹, OR⁸, SR⁸, OR⁹, SR⁹, C(O)R⁸, OC(O)R⁸, COOR⁸, C(O)R⁹, OC(O)R⁹,COOR⁹, C(O)NR⁸R⁹, C(O)NR⁹R⁹, NR⁹C(O)R⁸, NR⁹C(O)R⁹, NR⁹C(O)NR⁸R⁹,NR⁹C(O)NR⁹R⁹, NR⁹(COOR⁸), NR⁹(COOR⁹), OC(O)NR⁸R⁹, OC(O)NR⁹R⁹, S(O)₂R⁸,S(O)₂NR⁸R⁹, S(O)₂R⁹, S(O)₂NR⁹R⁹, NR⁹S(O)₂NR⁸R⁹, NR⁹S(O)₂NR⁹R⁹,NR⁹S(O)₂R⁸, NR⁹S(O)₂R⁹, R⁸ or R⁹;

R⁸ is a partially or fully saturated or fully unsaturated 3-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, andwherein each ring of said ring system is optionally substitutedindependently with 1-5 substituents of R⁹, oxo, NR⁹R⁹, OR⁹, SR⁹, C(O)R⁹,COOR⁹, C(O)NR⁹R⁹, NR⁹C(O)R⁹, NR⁹C(O)NR⁹R⁹, OC(O)NR⁹R⁹, S(O)₂R⁹,S(O)₂NR⁹R⁹, NR⁹S(O)₂R⁹, or a partially or fully saturated or unsaturated5-6 membered ring of carbon atoms optionally including 1-3 heteroatomsselected from O, N, or S, and optionally substituted independently with1-3 substituents of R⁹;

alternatively, R⁷ and R⁸ taken together form a saturated or partially orfully unsaturated 5-6 membered monocyclic or 7-10 membered bicyclic ringof carbon atoms optionally including 1-3 heteroatoms selected from O, N,or S, and the ring optionally substituted independently with 1-5substituents of R⁹;

R⁹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, oxo, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl,C₁₋₁₀-thioalkoxyl, —SO₂C₁₋₁₀-alkyl or a saturated or partially or fullyunsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14membered tricyclic ring system, said ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms ifbicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selectedfrom O, N, or S, wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and each ring ofsaid ring system is optionally substituted independently with 1-3substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl;

X is O or S; and

n is 0, 1 or 2.

In one embodiment, the invention provides compounds of Formula I whereinA is CR⁵ or N, in conjunction with any of the above or belowembodiments.

In one embodiment, the invention provides compounds of Formula I whereinA is CR⁵, in conjunction with any of the above or below embodiments.

In one embodiment, the invention provides compounds of Formula I whereinA is CR⁵ wherein R⁵ is H, halo, haloalkyl or C₁₋₃alkyl, in conjunctionwith any of the above or below embodiments.

In one embodiment, the invention provides compounds of Formula I whereinA is CR⁵ wherein R⁵ is H, F, Cl, methyl or ethyl, in conjunction withany of the above or below embodiments.

In one embodiment, the invention provides compounds of Formula I whereinA is CH, in conjunction with any of the above or below embodiments.

In one embodiment, the invention provides compounds of Formula I whereinA is N, in conjunction with any of the above or below embodiments.

In one embodiment, the invention provides compounds of Formula I whereinR¹ is C₁₋₈-alkyl, —OC₁₋₈-alkyl, —SC₁₋₈-alkyl, —NHC₁₋₈alkyl,N(C₁₋₈-alkyl)₂, C₂₋₈-alkenyl, C₂₋₈-alkynyl or C₃₋₈-cycloalkyl, each ofwhich is optionally substituted with 1-5 substituents of R⁹, inconjunction with any of the above or below embodiments.

In another embodiment, the invention provides compounds of Formula Iwherein R¹ is C₁₋₆-alkyl, —OC₁₋₆-alkyl, —SC₁₋₆-alkyl, —NHC₁₋₆-alkyl,—N(C₁₋₆-alkyl)₂, C₂₋₆-alkenyl, C₂₋₆-alkynyl or C₃₋₆-cycloalkyl, each ofwhich is optionally substituted with 1-5 substituents of R⁹, inconjunction with any of the above or below embodiments.

In another embodiment, the invention provides compounds of Formula Iwherein R¹ is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl,tert-butyl, pentyl, neo-pentyl, isopentyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, —OC₁₋₄-alkyl, —SC₁₋₄-alkyl, —NHC₁₋₄-alkyl or—N(C₁₋₄-alkyl)₂, each of which is optionally substituted with 1-5substituents of R⁹, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I includes compoundswherein R¹ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, pentyl, neopenyl, hexyl, cyclopropyl, cyclopentyl, cyclohexylor allyl, each of which is optionally comprising 1-4 heteroatomsselected from N, O and S and optionally substituted with one or moresubstituents of R⁹, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention provides compounds of Formula Iwherein R¹ is a 3-8 membered monocyclic or 6-12 membered bicyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, saidheteroatoms selected from O, N, or S, wherein said ring system isoptionally substituted independently with 1-5 substituents of R⁹, inconjunction with any of the above or below embodiments.

In another embodiment, the invention provides compounds of Formula Iwherein R¹ is a phenyl, pyridyl, pyrimidyl, triazinyl, pyridazinyl,pyrazinyl, thiophenyl, furyl, tetrahydrofuryl, pyrrolyl,tetrahydropyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl,thiazolyl, oxazolyl, oxazolinyl, isoxazolyl, isoxazolinyl, oxadiazolyl,isothiazolyl, morpholinyl, piperidinyl, piperazinyl, pyranyl,cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which isoptionally substituted independently with 1-5 substituents of R⁹, inconjunction with any of the above or below embodiments.

In another embodiment, the invention provides compounds of Formula Iwherein R¹ is a phenyl, pyridyl, pyrimidyl, triazinyl, pyridazinyl,pyrazinyl, thiophenyl, furyl, tetrahydrofuryl, pyrrolyl, pyrazolyl,imidazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl,oxadiazolyl, isothiazolyl, morpholinyl, piperidinyl, piperazinyl, eachof which is optionally substituted independently with 1-5 substituentsof R⁹, in conjunction with any of the above or below embodiments.

In another embodiment, the invention provides compounds of Formula Iwherein R¹ is a phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl,thiophenyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, morpholinyl,piperidinyl, piperazinyl, each of which is optionally substitutedindependently with 1-5 substituents of R⁹, in conjunction with any ofthe above or below embodiments.

In another embodiment, the invention provides compounds of Formula Iwherein R¹ is a phenyl, pyridyl, pyrimidyl, pyridazinyl or pyrazinyl,each of which is optionally substituted independently with 1-5substituents of R⁹, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention provides compounds of Formula Iwherein R¹ is a phenyl optionally substituted independently with 1-5substituents of R⁹, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention provides compounds of Formula Iwherein R¹ is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl,tert-butyl, pentyl, neo-pentyl, isopentyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, —OC₁₋₄-alkyl, —SC₁₋₄-alkyl, —NHC₁₋₄-alkyl or—N(C₁₋₄-alkyl)₂, each of which is optionally substituted with 1-5substituents of R⁹, or R¹ is a ring selected from phenyl, pyridyl,pyrimidyl, triazinyl, pyridazinyl, pyrazinyl, thiophenyl, furyl,tetrahydrofuryl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl,thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, morpholinyl,piperidinyl, piperazinyl, each ring of which is optionally substitutedindependently with 1-5 substituents of R⁹, in conjunction with any ofthe above or below embodiments.

In another embodiment, the invention provides compounds of Formula Iwherein R² is H, halo, haloalkyl, NO₂, CN, C₁₋₆-alkoxyl, C₁₋₆-thioalkyl,C₁₋₆-aminoalkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl or C₃₋₆-cycloalkyl, each ofthe C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl and C₃₋₁₀-cycloalkyloptionally substituted with 1-5 substituents of R⁹, in conjunction withany of the above or below embodiments.

In another embodiment, the invention provides compounds of Formula Iwherein R² is H, halo, haloalkyl, NO₂, CN, C₁₋₆-alkoxyl orC₁₋₆-aminoalkyl, each of which are optionally substituted with 1-5substituents of R⁹, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention provides compounds of Formula Iwherein R² is H, halo, haloalkyl or C₁₋₆-alkyl, in conjunction with anyof the above or below embodiments.

In another embodiment, the invention provides compounds of Formula Iwherein R² is H, halo, methyl or ethyl, in conjunction with any of theabove or below embodiments.

In another embodiment, the invention provides compounds of Formula Iwherein R² is H, F, Cl, methyl or ethyl, in conjunction with any of theabove or below embodiments.

In another embodiment, the invention provides compounds of Formula Iwherein R² is H, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention provides compounds of Formula Iwherein R³ is H, halo, haloalkyl, NO₂, CN, C₁₋₆-alkoxyl, C₁₋₆-thioalkyl,C₁₋₆-aminoalkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl or C₃₋₆-cycloalkyl, each ofthe C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl and C₃₋₁₀-cycloalkyloptionally substituted with 1-5 substituents of R⁹, in conjunction withany of the above or below embodiments.

In another embodiment, the invention provides compounds of Formula Iwherein R³ is H, halo, haloalkyl, NO₂, CN, C₁₋₆-alkoxyl orC₁₋₆-aminoalkyl, each of which are optionally substituted with 1-5substituents of R⁹, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention provides compounds of Formula Iwherein R³ is H, halo, haloalkyl or C₁₋₆-alkyl, in conjunction with anyof the above or below embodiments.

In another embodiment, the invention provides compounds of Formula Iwherein R³ is H, halo, methyl or ethyl, in conjunction with any of theabove or below embodiments.

In another embodiment, the invention provides compounds of Formula Iwherein R³ is H, F, Cl, methyl or ethyl, in conjunction with any of theabove or below embodiments.

In another embodiment, the invention provides compounds of Formula Iwherein R³ is H, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention provides compounds of Formula Iwherein each of R² and R³, independently, is H or halo, in conjunctionwith any of the above or below embodiments.

In another embodiment, the invention provides compounds of Formula Iwherein each of R² and R³, independently, is H, F, Cl, methyl or ethyl,in conjunction with any of the above or below embodiments.

In another embodiment, the invention provides compounds of Formula Iwherein each of R² and R³, independently, is H or F, in conjunction withany of the above or below embodiments.

In another embodiment, the invention provides compounds of Formula Iwherein each of R² and R³, independently, is H, in conjunction with anyof the above or below embodiments.

In another embodiment, the invention provides compounds of Formula Iwherein R⁴ is CN, C(O)R⁹, C₁₋₆-alkyl, —OC₁₋₆-alkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl or C₃₋₆-cycloalkyl, each of the C₁₋₆-alkyl, —OC₁₋₆-alkyl,C₂₋₆-alkenyl, C₂₋₁₀-alkynyl and C₃₋₆-cycloalkyl optionally substitutedwith 1-5 substituents of R⁹, in conjunction with any of the above orbelow embodiments.

In another embodiment, the invention provides compounds of Formula Iwherein R⁴ is CN, C(O)R⁹, —OC₁₋₆-alkyl, C₁₋₄-alkylC(O)R⁹, methyl, ethyl,propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, pentyl,neopentyl or C₁₋₄-alkyl-amino-C₁₋₄-alkyl orC₁₋₁₀-dialkylaminoC₁₋₄-alkyl-, in conjunction with any of the above orbelow embodiments.

In another embodiment, the invention provides compounds of Formula Iwherein R⁴ is —OC₁₋₆-alkyl, C₁₋₄-alkylC(O)R⁹, methyl, ethyl, propyl,isopropyl, cyclopropyl, butyl, isobutyl, pentyl orC₁₋₄-alkyl-amino-C₁₋₄-alkyl or C₁₋₄-dialkylaminoC₁₋₄-alkyl-, inconjunction with any of the above or below embodiments.

In another embodiment, the invention provides compounds of Formula Iwherein wherein R⁴ is methyl, ethyl, propyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, pentyl or neopentyl, in conjunction withany of the above or below embodiments.

In another embodiment, the invention provides compounds of Formula Iwherein wherein R⁴ is methyl, ethyl, propyl, butyl, isobutyl or pentyl,in conjunction with any of the above or below embodiments.

In another embodiment, the invention provides compounds of Formula Iwherein wherein R⁴ is methyl, in conjunction with any of the above orbelow embodiments.

In another embodiment, the invention provides compounds of Formula Iwherein each R⁵, independently, is H, halo, haloalkyl, NO₂, CN, OH,C₁₋₆-alkyl, —OC₁₋₆-alkyl, —SC₁₋₆-alkyl, —NHC₁₋₆-alkyl, wherein theC₁₋₆-alkyl of each is optionally comprising 1-3 heteroatoms selectedfrom N, O and S and optionally substituted with 1-5 substituents of R⁹,in conjunction with any of the above or below embodiments.

In another embodiment, the invention provides compounds of Formula Iwherein each R⁵, independently, is H, F, Cl, Br, CF₃, —OCF₃, C₂F₅,—OC₂F₅, —OC₁₋₆-alkyl, —C₁₋₄-alkyl-O—C₁₋₆-alkyl, —SC₁₋₆-alkyl,—C₁₋₄-alkyl-S—C₁₋₆-alkyl, —NHC₁₋₆-alkyl, —N(C₁₋₆-alkyl)₂,—C₁₋₄-alkkyl-NH—C₁₋₆-alkyl, C₁₋₃-alkyl-N(C₁₋₄-alkyl)₂, NO₂, NH₂, CN orC₁₋₆-alkyl optionally substituted with 1-3 substituents of R⁹, inconjunction with any of the above or below embodiments.

In another embodiment, the invention provides compounds of Formula Iwherein each R⁵, independently, is H, F, Cl, Br, CF₃, —OCF₃, C₂F₅,—OC₂F₅, —OCH₃, —SCH₃, —NHCH₃, NO₂, NH₂, OH, CN, methyl, ethyl or propyl,in conjunction with any of the above or below embodiments.

In another embodiment, the invention provides compounds of Formula Iwherein each R⁵, independently, is H, F, Cl, Br, CF₃, —OCH₃, —NHCH₃, OH,CN, methyl or ethyl, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention provides compounds of Formula Iwherein each R⁵, independently, is H, F, Cl, Br, OH, CN or methyl, inconjunction with any of the above or below embodiments.

In another embodiment, the invention provides compounds of Formula Iwherein R⁶ is C(O)NR⁷R⁷, C(O)NR⁷R⁸, NR⁷C(O)R⁷, NR⁷C(O)R⁸, NR⁷C(O)NR⁷R⁷,NR⁷C(O)NR⁷R⁸, S(O)₂NR⁷R⁷, S(O)₂NR⁷R⁸, NR⁷S(O)₂NR⁷R⁸, NR⁷S(O)₂R⁷ orNR⁷S(O)₂R⁸, in conjunction with any of the above or below embodiments.

In another embodiment, the invention provides compounds of Formula Iwherein R⁶ is C(O)NR⁷R⁷, C(O)NR⁷R⁸, NR⁷C(O)R⁷, NR⁷C(O)R⁸, S(O)₂NR⁷R⁷,S(O)₂NR⁷R⁸, NR⁷S(O)₂R⁷ or NR⁷S(O)₂R⁸, in conjunction with any of theabove or below embodiments.

In another embodiment, the invention provides compounds of Formula Iwherein R⁶ is C(O)NR⁷R⁷, C(O)NR⁷R⁸, NR⁷C(O)R⁷ or NR⁷C(O)R⁸, inconjunction with any of the above or below embodiments.

In another embodiment, the invention provides compounds of Formula Iwherein R⁶ is C(O)NHC₁₋₆-alkyl, C(O)NHC₂₋₆-alkenyl, C(O)NHC₂₋₆-alkynyl,C(O)NHC₃₋₆-cycloalkyl, C(O)NHaryl, C(O)NHheteroaryl, NHC(O)C₁₋₆-alkyl,NHC(O)C₂₋₆-alkenyl, NHC(O)C₂₋₆-alkynyl, NHC(O)C₃₋₆-cycloalkyl,NHC(O)aryl or NHC(O)heteroaryl, in conjunction with any of the above orbelow embodiments.

In another embodiment, the invention provides compounds of Formula Iwherein R⁶ is C(O)NR⁷R⁷ or C(O)NR⁷R⁸, in conjunction with any of theabove or below embodiments.

In another embodiment, the invention provides compounds of Formula Iwherein R⁸ is a ring selected from phenyl, naphthyl, pyridyl, pyrimidyl,triazinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl,quinazolinyl, isoquinazolinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl,imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl,indolyl, isoindolyl, benzofuranyl, benzothiophenyl, benzimidazolyl,benzoxazolyl, benzisoxazolyl, benzopyrazolyl, benzothiazolyl,tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, isoxazolinyl, thiazolinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl,wherein said ring is optionally substituted independently with 1-3substituents of R⁹, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention provides compounds of Formula Iwherein R⁸ is a ring selected from phenyl, pyridyl, pyrimidyl,triazinyl, pyridazinyl, pyrazinyl, thiophenyl, furyl, pyrrolyl,pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl,isothiazolyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, isoxazolinyl,thiazolinyl, pyrazolinyl, morpholinyl, piperidinyl, piperazinyl,pyranyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andcycloheptyl, wherein said ring is optionally substituted independentlywith 1-3 substituents of R⁹, in conjunction with any of the above orbelow embodiments.

In another embodiment, the invention provides compounds of Formula Iwherein X is O or S, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention provides compounds of Formula Iwherein X is O, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention provides compounds of Formula Iwherein X is S, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention provides compounds of Formula Iwherein

A is CH or N;

R¹ is phenyl, pyridyl, pyrimidyl, triazinyl, pyridazinyl, pyrazinyl,thiophenyl, furyl, tetrahydrofuryl, pyrrolyl, tetrahydropyrrolyl,pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl,oxazolinyl, isoxazolyl, isoxazolinyl, oxadiazolyl, isothiazolyl,morpholinyl, piperidinyl, piperazinyl, pyranyl, cyclopropyl, cyclobutyl,cyclopentyl or cyclorhexyl, each of which is optionally substituted with1-5 substituents of R⁹;

each of R² and R³, independently, is H, halo, haloalkyl or C₁₋₄-alkyl;

R⁴ is CN, C(O)R⁷, —OC₁₋₆-alkyl, C₁₋₄-alkylC(O)R⁷, methyl, ethyl, propyl,isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentylor C₁₋₄-alkyl-amino-C₁₋₄-alkyl or C₁₋₁₀-dialkylaminoC₁₋₄-alkyl-;

each R⁵, independently, is H, F, Cl, Br, CF₃, —OCF₃, C₂F₅, —OC₂F₅,—O—C₁₋₆-alkyl, —C₁₋₄-alkyl-O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl,—C₁₋₄-alkyl-S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl, —N(C₁₋₆-alkyl)₂,—C₁₋₄-alkyl-NH—C₁₋₆-alkyl, —C₁₋₃-alkyl-N(C₁₋₄-alkyl)₂, NO₂, NH₂, CN orC₁₋₁₀-alkyl, the C₁₋₁₀-alkyl optionally substituted with one or moresubstituents of R⁷;

R⁶ is C(O)NR⁷R⁷, C(O)NR⁷R⁸, NR⁷C(O)R⁷, NR⁷C(O)R⁸, S(O)₂NR⁷R⁷,S(O)₂NR⁷R⁸, NR⁷S(O)₂R⁷ or NR⁷S(O)₂R⁸;

each R⁷, independently, is H, C₁₋₁₀-alkyl or C₃₋₁₀-cycloalkyl, whereinthe C₁₋₁₀-alkyl and C₃₋₁₀-cycloalkyl optionally comprising 1-4heteroatoms selected from N, O and S and optionally substituted with 1-3substituents of R⁹;

R⁸ is a ring selected from phenyl, naphthyl, pyridyl, pyrimidyl,triazinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl,quinazolinyl, isoquinazolinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl,imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl,indolyl, isoindolyl, benzofuranyl, benzothiophenyl, benzimidazolyl,benzoxazolyl, benzisoxazolyl, benzopyrazolyl, benzothiazolyl,tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, isoxazolinyl, thiazolinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl,wherein said ring is optionally substituted independently with 1-3substituents of R⁹; and

R⁹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, oxo, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl,C₁₋₁₀-thioalkoxyl, —SO₂C₁₋₁₀-alkyl or a saturated or partially or fullyunsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14membered tricyclic ring system, said ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms ifbicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selectedfrom O, N, or S, wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and each ring ofsaid ring system is optionally substituted independently with 1-3substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl;

X is O; and

n is 0 or 1.

In another embodiment, the invention provides compounds of Formula Iwherein

A is CH;

R¹ is C₁₋₆-alkyl, —OC₁₋₆-alkyl, —SC₁₋₆-alkyl, —NHC₁₋₆-alkyl or a ringselected from phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl,thiophenyl, furyl, tetrahydrofuryl, pyrrolyl, tetrahydropyrrolyl,pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl,isothiazolyl, morpholinyl, piperidinyl, piperazinyl, cyclopropyl,cyclobutyl, cyclopentyl or cyclorhexyl, each of C₁₋₆-alkyl,—OC₁₋₆-alkyl, —SC₁₋₆-alkyl, —NHC₁₋₆-alkyl and ring optionallysubstituted with 1-5 substituents of R⁹;

each of R² and R³, independently, is H, F, Cl, CF₃, methyl or ethyl;

R⁴ is CN, C(O)R⁷, —OC₁₋₆-alkyl, C₁₋₄-alkylC(O)R⁷, methyl, ethyl, propyl,isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, pentyl,C₁₋₄-alkyl-amino-C₁₋₄-alkyl or C₁₋₄-dialkylaminoC₁₋₄-alkyl-;

each R⁵, independently, is H, F, Cl, Br, CF₃, —OCF₃, C₂F₅, —OC₂F₅, OH,—O-methyl, —S-methyl, —NH-methyl, —N(methyl)₂, NO₂, NH₂, CN orC₁₋₆-alkyl, the C₁₋₆-alkyl optionally substituted with one or moresubstituents of R⁹;

R⁶ is C(O)NR⁷R⁷, C(O)NR⁷R⁸, NR⁷C(O)R⁷ or NR⁷C(O)R⁸;

each R⁷, independently, is H, C₁₋₆-alkyl or C₃₋₆-cycloalkyl, wherein theC₁₋₆-alkyl and C₃₋₆-cycloalkyl optionally comprising 1-3 heteroatomsselected from N, O and S and optionally substituted with 1-3substituents of R⁹;

R⁸ is a ring selected from phenyl, naphthyl, pyridyl, pyrimidyl,triazinyl, pyridazinyl, pyrazinyl, thiophenyl, furyl, pyrrolyl,pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl,isoxazolyl, isothiazolyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl,isoxazolinyl, thiazolinyl, pyrazolinyl, morpholinyl, piperidinyl,piperazinyl, pyranyl, dioxozinyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl, wherein said ring is optionally substitutedindependently with 1-3 substituents of R⁹;

R⁹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, oxo, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl,C₁₋₁₀-thioalkoxyl, —SO₂C₁₋₁₀-alkyl or a saturated or partially or fullyunsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14membered tricyclic ring system, said ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms ifbicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selectedfrom O, N, or S, wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and each ring ofsaid ring system is optionally substituted independently with 1-3substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl;

X is O; and

n is 0 or 1.

In another embodiment, the invention provides compounds of Formula Iwherein

A is CH;

R¹ is phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, thiophenyl,furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl,oxazolinyl, isoxazolyl, isoxazolinyl, oxadiazolyl or isothiazolyl, eachof which is optionally substituted independently with 1-3 substituentsof R⁹;

each of R² and R³, independently, is H, F, Cl, CF₃ or methyl;

R⁴ is CN, —C(O)methyl, —OC₁₋₆-alkyl, C₁₋₄-alkylC(O)R⁷, methyl, ethyl,propyl, isopropyl, butyl, pentyl, C₁₋₄-alkyl-amino-C₁₋₄-alkyl orC₁₋₄-dialkylaminoC₁₋₄-alkyl-;

each R⁵, independently, is H, F, Cl, Br, CF₃, —OCF₃, C₂F₅,—O—C₁₋₃-alkyl, —S—C₁₋₃-alkyl, —NH—C₁₋₃-alkyl, NO₂, NH₂, OH, CN, methyl,ethyl propyl or isopropyl;

R⁶ is C(O)NR⁷R⁷, C(O)NR⁷R⁸, NR⁷C(O)R⁷ or NR⁷C(O)R⁸;

each R⁷, independently, is H, methyl, ethyl, propyl, isopropyl,cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of thecyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl optionallysubstituted with 1-3 substituents of R⁹;

R⁸ is a ring selected from phenyl, pyridyl, pyrimidyl, triazinyl,pyridazinyl, pyrazinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl,imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl,tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, isoxazolinyl, thiazolinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl,wherein said ring is optionally substituted independently with 1-3substituents of R⁹;

R⁹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, oxo, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl,C₁₋₁₀-thioalkoxyl, —SO₂C₁₋₁₀-alkyl or a saturated or partially or fullyunsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14membered tricyclic ring system, said ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms ifbicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selectedfrom O, N, or S, wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and each ring ofsaid ring system is optionally substituted independently with 1-3substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl;

X is O; and

n is 0 or 1.

In another embodiment, the invention provides compounds of Formula I,and pharmaceutically acceptable salts thereof, selected from

-   N-cyclopropyl-3-(8-(2,4-difluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazin-3-yl)-4-methylbenzamide;-   3-(8-(2,4-difluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazin-3-yl)-4-methylbenzamide;-   N-cyclopropyl-3-(8-(2,4-difluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazin-3-yl)-5-fluoro-4-methylbenzamide;-   4-chloro-N-cyclopropyl-3-(8-(2,4-difluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazin-3-yl)benzamide;-   N-cyclopropyl-4-methyl-3-(1-methyl-2-oxo-8-o-tolyl-1,2-dihydropyrido[3,2-d]pyridazin-3-yl)benzamide;-   N-cyclopropyl-3-fluoro-4-methyl-5-(1-methyl-2-oxo-8-o-tolyl-1,2-dihydropyrido[3,2-d]pyridazin-3-yl)benzamide;-   3-(8-(2-chlorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazin-3-yl)-N-cyclopropyl-4-methylbenzamide;-   N-cyclopropyl-3-(8-(2-fluoro-4-(trifluoromethyl)phenyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazin-3-yl)-4-methylbenzamide;-   N-cyclopropyl-4-methyl-3-(1-methyl-2-oxo-8-(2-(trifluoromethyl)phenyl)-1,2-dihydropyrido[3,2-d]pyridazin-3-yl)benzamide;-   N-cyclopropyl-3-fluoro-4-methyl-5-(1-methyl-2-oxo-8-(2-(trifluoromethyl)phenyl)-1,2-dihydropyrido[3,2-d]pyridazin-3-yl)benzamide;-   N-cyclopropyl-3-(8-(4-fluoro-2-methylphenyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazin-3-yl)-4-methylbenzamide;-   3-(8-(2-chloro-4-fluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-N-cyclopropyl-4-methylbenzamide;-   3-(8-(2-chlorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-N-cyclopropyl-5-fluoro-4-methylbenzamide;-   3-(8-(2,4-difluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-4-methyl-N-(1-methyl-1H-pyrazol-5-yl)benzamide;-   N-cyclopropyl-3-fluoro-5-(8-(4-fluoro-2-methylphenyl)-1-methyl-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-4-methylbenzamide;-   3-(8-(2-chloro-4-fluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-N-cyclopropyl-5-fluoro-4-methylbenzamide;-   3-(8-(2-chloro-5-fluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-N-cyclopropyl-4-methylbenzamide;-   3-(8-(2-chloro-5-fluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-N-cyclopropyl-5-fluoro-4-methylbenzamide;-   3-(8-(2-chloro-4-fluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-4-methyl-N-(1-methylcyclopropyl)benzamide;-   3-(8-(2-chloro-4-fluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-N-3-isoxazolyl-4-methylbenzamide;-   N-cyclopropyl-3-(8-(2,4-difluorophenyl)-1-ethyl-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-5-fluoro-4-methylbenzamide;-   N-cyclopropyl-3-(8-(2,4-difluorophenyl)-1-ethyl-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-4-methylbenzamide;-   3-(8-(2-chloro-4-fluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-4-methyl-N-1,3-thiazol-2-ylbenzamide;-   3-(8-(2-chlorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-N-3-isoxazolyl-4-methylbenzamide;-   N-cyclopropyl-4-methyl-3-(1-methyl-8-(2-methyl-4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)benzamide;-   N-cyclopropyl-3-fluoro-4-methyl-5-(1-methyl-8-(2-methyl-4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)benzamide;-   3-(8-(2-chlorophenyl)-1-ethyl-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-N-cyclopropyl-4-methylbenzamide;-   N-cyclopropyl-4-(8-(2,4-difluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-5-methyl-2-pyridinecarboxamide;-   3-(8-(2,4-difluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-N,4-dimethylbenzamide;-   3-(8-(2,4-difluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-4-methyl-N-1,3-thiazol-2-ylbenzamide;    and-   3-(8-(2,4-difluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-N-3-isoxazolyl-4-methylbenzamide.

In another embodiment, the invention provides the compoundN-cyclopropyl-3-(8-(2,4-difluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazin-3-yl)-4-methylbenzamide,or a pharmaceutically acceptable salt form thereof.

In another embodiment, the invention provides the compoundN-cyclopropyl-3-(8-(2,4-difluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazin-3-yl)-5-fluoro-4-methylbenzamide,or a pharmaceutically acceptable salt form thereof.

In another embodiment, the invention provides the compoundN-cyclopropyl-4-methyl-3-(1-methyl-2-oxo-8-o-tolyl-1,2-dihydropyrido[3,2-d]pyridazin-3-yl)benzamide,or a pharmaceutically acceptable salt form thereof.

In another embodiment, the invention provides the compoundN-cyclopropyl-3-fluoro-4-methyl-5-(1-methyl-2-oxo-8-o-tolyl-1,2-dihydropyrido[3,2-d]pyridazin-3-yl)benzamide,or a pharmaceutically acceptable salt form thereof.

In another embodiment, the invention provides the compound3-(8-(2-chlorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazin-3-yl)-N-cyclopropyl-4-methylbenzamide,or a pharmaceutically acceptable salt form thereof.

In another embodiment, the invention provides the compoundN-cyclopropyl-3-(8-(2-fluoro-4-(trifluoromethyl)phenyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazin-3-yl)-4-methylbenzamide,or a pharmaceutically acceptable salt form thereof.

In another embodiment, the invention provides the compoundN-cyclopropyl-4-methyl-3-(1-methyl-2-oxo-8-(2-(trifluoromethyl)phenyl)-1,2-dihydropyrido[3,2-d]pyridazin-3-yl)benzamide,or a pharmaceutically acceptable salt form thereof.

In another embodiment, the invention provides the compoundN-cyclopropyl-3-(8-(4-fluoro-2-methylphenyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazin-3-yl)-4-methylbenzamide,or a pharmaceutically acceptable salt form thereof.

In another embodiment, the invention provides the compound3-(8-(2-chlorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-N-cyclopropyl-5-fluoro-4-methylbenzamide,or a pharmaceutically acceptable salt form thereof.

In another embodiment, the invention provides the compound3-(8-(2-chloro-4-fluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-N-cyclopropyl-5-fluoro-4-methylbenzamide,or a pharmaceutically acceptable salt form thereof.

In another embodiment, the invention provides the compound3-(8-(2-chloro-5-fluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-N-cyclopropyl-4-methylbenzamide,or a pharmaceutically acceptable salt form thereof.

In another embodiment, the invention provides the compound3-(8-(2-chloro-4-fluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-N-3-isoxazolyl-4-methylbenzamide,or a pharmaceutically acceptable salt form thereof.

In another embodiment, the invention provides the compound3-(8-(2-chlorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-N-3-isoxazolyl-4-methylbenzamide,or a pharmaceutically acceptable salt form thereof.

In another embodiment, the invention provides a compound of Formula I-A

or a pharmaceutically acceptable salt thereof, wherein

R¹ is C₁₋₆-alkyl, —OC₁₋₆-alkyl, —SC₁₋₆-alkyl, —NHC₁₋₆-alkyl or a ringselected from phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl,thiophenyl, furyl, tetrahydrofuryl, pyrrolyl, tetrahydropyrrolyl,pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl,isothiazolyl, morpholinyl, piperidinyl, piperazinyl, cyclopropyl,cyclobutyl, cyclopentyl or cyclorhexyl, each of C₁₋₆-alkyl,—OC₁₋₆-alkyl, —SC₁₋₆-alkyl, —NHC₁₋₆-alkyl and ring optionallysubstituted with 1-5 substituents of R⁹;

each of R² and R³, independently, is H or halo;

R⁴ is CN, C(O)R⁷, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl orC₃₋₈-cycloalkyl, each of the C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl andC₃₋₈-cycloalkyl optionally comprising 1-4 heteroatoms selected from N, Oand S and optionally substituted with one or more substituents of R⁹;

each R⁵, independently, is H, halo, haloalkyl, NO₂, CN, OR⁷, NR⁷R⁷ orC₁₋₆-alkyl;

R⁶ is C(O)NR⁷R⁷ or C(O)NR⁷R⁸;

each R⁷, independently, is H, C₁₋₆-alkyl or C₃₋₆-cycloalkyl, each of theC₁₋₆-alkyl, and C₃₋₆-cycloalkyl optionally substituted with one or moresubstituents of R⁹;

R⁸ is a ring selected from phenyl, naphthyl, pyridyl, pyrimidyl,triazinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl,quinazolinyl, isoquinazolinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl,imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl,indolyl, isoindolyl, benzofuranyl, benzothiophenyl, benzimidazolyl,benzoxazolyl, benzisoxazolyl, benzopyrazolyl, benzothiazolyl,tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, isoxazolinyl, thiazolinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl,wherein said ring is optionally substituted independently with 1-3substituents of R⁹; and

R⁹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, oxo, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl,C₁₋₁₀-thioalkoxyl, —SO₂C₁₋₁₀-alkyl or a saturated or partially or fullyunsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14membered tricyclic ring system, said ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms ifbicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selectedfrom O, N, or S, wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and each ring ofsaid ring system is optionally substituted independently with 1-3substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl.

In another embodiment, the invention provides compounds of Formula I-A,or a pharmaceutically acceptable salt thereof, wherein

R¹ is phenyl, pyridyl, pyrimidyl, triazinyl, pyridazinyl, pyrazinyl,thiophenyl, furyl, tetrahydrofuryl, pyrrolyl, tetrahydropyrrolyl,pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl,oxazolinyl, isoxazolyl, isoxazolinyl, oxadiazolyl, isothiazolyl,morpholinyl, piperidinyl, piperazinyl, pyranyl, cyclopropyl, cyclobutyl,cyclopentyl or cyclorhexyl, each of which is optionally substituted with1-5 substituents of R⁹;

each of R² and R³, independently, is H, F or Cl;

R⁴ is CN, C(O)CH₃, C₁₋₄-alkylC(O)R⁷, methyl, ethyl, propyl, isopropyl orC₁₋₄-alkyl-amino-C₁₋₄-alkyl or C₁₋₁₀-dialkylaminoC₁₋₄-alkyl-;

each R⁵, independently, is H, CH₃, C₂H₅, F, Cl, Br, CF₃, —OCF₃, C₂F₅,—OC₂F₅, —OCH₃, —SCH₃ or —NHCH₃;

R⁶ is C(O)NR⁷R⁸;

R⁷ is H or CH₃;

R⁸ is a ring selected from phenyl, naphthyl, pyridyl, pyrimidyl,triazinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl,quinazolinyl, isoquinazolinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl,imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl,indolyl, isoindolyl, benzofuranyl, benzothiophenyl, benzimidazolyl,benzoxazolyl, benzisoxazolyl, benzopyrazolyl, benzothiazolyl,tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, isoxazolinyl, thiazolinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl,wherein said ring is optionally substituted independently with 1-3substituents of R⁹; and

R⁹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, oxo, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl,C₁₋₁₀-thioalkoxyl, —SO₂C₁₋₁₀-alkyl or a saturated or partially or fullyunsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14membered tricyclic ring system, said ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms ifbicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selectedfrom O, N, or S, wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and each ring ofsaid ring system is optionally substituted independently with 1-3substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl.

In another embodiment, the invention provides a compound of Formula I-B

or a pharmaceutically acceptable salt thereof, wherein

R¹ is H, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl or C₃₋₁₀-cycloalkyl,each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyland C₄₋₁₀-cycloalkenyl optionally comprising 1-4 heteroatoms selectedfrom N, O and S and optionally substituted with one or more substituentsof R⁹,

or R¹ is a 3-8 membered monocyclic or 6-12 membered bicyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, saidheteroatoms selected from O, N, or S, wherein said ring system isoptionally substituted independently with one or more substituents ofR⁹;

each of R² and R³, independently, is H or halo;

R⁴ is CN, C(O)R⁷, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl orC₃₋₈-cycloalkyl, each of the C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl andC₃₋₈-cycloalkyl optionally comprising 1-4 heteroatoms selected from N, Oand S and optionally substituted with one or more substituents of R⁹;

each R⁵, independently, is H, halo, haloalkyl, NO₂, CN, OR⁷, NR⁷R⁷ orC₁₋₆-alkyl;

each R⁷, independently, is H, C₁₋₆-alkyl or C₃₋₆-cycloalkyl, each of theC₁₋₆-alkyl, and C₃₋₆-cycloalkyl optionally substituted with one or moresubstituents of R⁹; and

R⁹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, oxo, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl,C₁₋₁₀-thioalkoxyl, —SO₂C₁₋₁₀-alkyl or a saturated or partially or fullyunsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14membered tricyclic ring system, said ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms ifbicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selectedfrom O, N, or S, wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and each ring ofsaid ring system is optionally substituted independently with 1-3substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl.

In another embodiment, the invention provides a compound of Formula I-C,

or a pharmaceutically acceptable salt thereof, wherein

R¹ is H, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl or C₃₋₁₀-cycloalkyl,each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyland C₄₋₁₀-cycloalkenyl optionally comprising 1-4 heteroatoms selectedfrom N, O and S and optionally substituted with one or more substituentsof R⁹,

or R¹ is a 3-8 membered monocyclic or 6-12 membered bicyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, saidheteroatoms selected from O, N, or S, wherein said ring system isoptionally substituted independently with one or more substituents ofR⁹;

each of R² and R³, independently, is H or F;

R⁴ is CN, C(O)R⁷, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl orC₃₋₈-cycloalkyl, each of the C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl andC₃₋₈-cycloalkyl optionally comprising 1-4 heteroatoms selected from N, Oand S and optionally substituted with one or more substituents of R⁹;

each R⁵, independently, is H, halo, haloalkyl, NO₂, CN, OR⁷, NR⁷R⁷ orC₁₋₆-alkyl;

R⁷ is H, C₁₋₆-alkyl or C₃₋₆-cycloalkyl, each of the C₁₋₆-alkyl, andC₃₋₆-cycloalkyl optionally substituted with one or more substituents ofR⁹;

R⁸ is a ring selected from phenyl, naphthyl, pyridyl, pyrimidyl,triazinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl,quinazolinyl, isoquinazolinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl,imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl,indolyl, isoindolyl, benzofuranyl, benzothiophenyl, benzimidazolyl,benzoxazolyl, benzisoxazolyl, benzopyrazolyl, benzothiazolyl,tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, isoxazolinyl, thiazolinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl,wherein said ring is optionally substituted independently with 1-3substituents of R⁹; and

R⁹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, oxo, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl,C₁₋₁₀-thioalkoxyl, —SO₂C₁₋₁₀-alkyl or a saturated or partially or fullyunsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14membered tricyclic ring system, said ring system formed of carbon atomsoptionally including 1-3 heteroatoms if mono cyclic, 1-6 heteroatoms ifbicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selectedfrom O, N, or S, wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and each ring ofsaid ring system is optionally substituted independently with 1-3substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl.

In yet another embodiment, the compounds of Formulas I, I-B and I-Cinclude each individual example, and each and every pharmaceuticallyacceptable salt form thereof, described hereinbelow.

In another embodiment of the invention, the compounds, includingstereoisomers, tautomers, solvates, pharmaceutically acceptable salts,derivatives or prodrugs thereof, are defined by general Formula II:

wherein

one of A¹, A² and A³ is N and the other two of A¹, A² and A³ is CR⁵;

R¹ is C₁₋₈-alkyl, —OC₁₋₈-alkyl, —SC₁₋₈-alkyl, —NHC₁₋₈-alkyl,—N(C₁₋₈-alkyl)₂, C₂₋₈-alkenyl, C₂₋₈-alkynyl or C₃₋₈-cycloalkyl, each ofwhich is optionally substituted with 1-5 substituents of R⁹,

or R¹ is a 3-8 membered monocyclic or 6-12 membered bicyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, saidheteroatoms selected from O, N, or S, wherein said ring system isoptionally substituted independently with 1-5 substituents of R⁹;

each of R² and R³, independently, is H, halo, haloalkyl, NO₂, CN,C₁₋₆-alkyl, C₁₋₆-alkoxyl, C₁₋₆-thioalkyl, C₁₋₆-aminoalkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl or C₃₋₆-cycloalkyl, each of the C₁₋₆-alkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl and C₃₋₁₀-cycloalkyl optionally substituted with 1-5substituents of R⁹;

R⁴ is CN, C(O)R⁹, C₁₋₆-alkyl, —OC₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynylor C₃₋₆-cycloalkyl, each of the C₁₋₆-alkyl, —OC₁₋₆-alkyl, C₂₋₆-alkenyl,C₂₋₁₀-alkynyl and C₃₋₆-cycloalkyl optionally substituted with 1-5substituents of R⁹;

each R⁵, independently, is H, halo, haloalkyl, NO₂, CN, OH, C₁₋₆-alkyl,—OC₁₋₆-alkyl, —SC₁₋₆-alkyl, —NHC₁₋₆-alkyl, wherein the C₁₋₆-alkyl ofeach is optionally comprising 1-3 heteroatoms selected from N, O and Sand optionally substituted with 1-5 substituents of R⁹;

R⁶ is C(O)NR⁷R⁷, C(O)NR⁷R⁸, NR⁷C(O)R⁷, NR⁷C(O)R⁸, NR⁷C(O)NR⁷R⁷,NR⁷C(O)NR⁷R⁸, S(O)₂NR⁷R⁷, S(O)₂NR⁷R⁸, NR⁷S(O)₂NR⁷R⁸, NR⁷S(O)₂R⁷ orNR⁷S(O)₂R⁸;

each R⁷, independently, is H, C₁₋₈-alkyl, C₂₋₈-alkenyl, C₂₋₈-alkynyl orC₃₋₈-cycloalkyl, each of the C₁₋₈-alkyl, C₂₋₈-alkenyl, C₂₋₈-alkynyl andC₃-cycloalkyl optionally comprising 1-4 heteroatoms selected from N, Oand S and optionally substituted with one or more substituents of NR⁸R⁹,NR⁹R⁹, OR^(B), SR⁸, OR⁹, SR⁹, C(O)R⁸, OC(O)R⁸, COOR^(S), C(O)R⁹,OC(O)R⁹, COOR⁹, C(O)NR⁸R⁹, C(O)NR⁹R⁹, NR⁹C(O)R⁸, NR⁹C(O)R⁹,NR⁹C(O)NR⁸R⁹, NR⁹C(O)NR⁹R⁹, NR⁹(COOR⁸), NR⁹(COOR⁹), OC(O)NR⁸R⁹,OC(O)NR⁹R⁹, S(O)₂R⁸, S(O)₂NR⁸R⁹, S(O)₂R⁹, S(O)₂NR⁹R⁹, NR⁹S(O)₂NR⁸R⁹,NR⁹S(O)₂NR⁹R⁹, NR⁹S(O)₂R⁸, NR⁹S(O)₂R⁹, R⁸ or R⁹;

R⁸ is a partially or fully saturated or fully unsaturated 3-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, andwherein each ring of said ring system is optionally substitutedindependently with 1-5 substituents of R⁹, oxo, NR⁹R⁹, OR⁹, SR⁹, C(O)R⁹,COOR⁹, C(O)NR⁹R⁹, NR⁹C(O)R⁹, NR⁹C(O)NR⁹R⁹, OC(O)NR⁹R⁹, S(O)₂R⁹,S(O)₂NR⁹R⁹, NR⁹S(O)₂R⁹, or a partially or fully saturated or unsaturated5-6 membered ring of carbon atoms optionally including 1-3 heteroatomsselected from O, N, or S, and optionally substituted independently with1-3 substituents of R⁹;

alternatively, R⁷ and R⁸ taken together form a saturated or partially orfully unsaturated 5-6 membered monocyclic or 7-10 membered bicyclic ringof carbon atoms optionally including 1-3 heteroatoms selected from O, N,or S, and the ring optionally substituted independently with 1-5substituents of R⁹;

R⁹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, oxo, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl,C₁₋₁₀-thioalkoxyl, —SO₂C₁₋₁₀-alkyl or a saturated or partially or fullyunsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14membered tricyclic ring system, said ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms ifbicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selectedfrom O, N, or S, wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and each ring ofsaid ring system is optionally substituted independently with 1-3substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl; and

X is O or S.

In another embodiment, the invention provides compounds of Formula IIwherein A¹ is CR⁵, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention provides compounds of Formula IIwherein A² is CR⁵, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention provides compounds of Formula IIwherein A³ is CR⁵, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention provides compounds of Formula IIwherein A¹ is N, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention provides compounds of Formula IIwherein A² is N, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention provides compounds of Formula IIwherein A³ is N, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention provides compounds of Formula IIwherein two of A¹, A² and A³, independently, is CR⁵ and the other one ofA¹, A² and A³, independently, as N, in conjunction with any of the aboveor below embodiments.

In another embodiment, the invention provides compounds of Formula IIwherein each of A¹ and A², independently, is CR⁵ wherein each R⁵,independently, is H, F, Cl, Br, CF₃, —OCF₃, C₂F₅, —OC₂F₅, —OCH₃, —SCH₃or —NHCH₃, and A³ is N, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention provides compounds of Formula IIwherein each of A¹ and A², independently, is CR⁵ wherein each R⁵,independently, is H, F, Cl, Br, CF₃, —OCF₃, C₂F₅, —OC₂F₅, —O—C₁₋₆-alkyl,—C₁₋₄-alkyl-O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl, —C₁₋₄-alkyl-S—C₁₋₆-alkyl,—N(C₁₋₆-alkyl)₂, —C₁₋₃-alkyl-N(C₁₋₄-alkyl)₂, NO₂, NH₂, CN orC₁₋₁₀-alkyl, and A³ is N, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention provides compounds of Formula IIwherein each of A¹ and A³, independently, is CR⁵ wherein each R⁵,independently, is H, F, Cl, Br, CF₃, —OCF₃, C₂F₅, —OC₂F₅, —O—C₁₋₄-alkyl,—S—C₁₋₄-alkyl, —NH—C₁₋₄-alkyl, OH, NO₂, NH₂, CN, methyl, ethyl orpropyl, and A² is N, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention provides compounds of Formula IIwherein each R⁵, independently, is H, F, Cl, Br, CF₃, —OCF₃, C₂F₅,—OC₂F₅, —OCH₃, —SCH₃ or —NHCH₃; and each of R² and R³, independently, isH, F or Cl, in conjunction with any of the above or below embodiments.

In another embodiment, the invention provides compounds of Formula IIwherein each of R² and R³, independently, is H, in conjunction with anyof the above or below embodiments.

In another embodiment, the invention provides compounds of Formula IIwherein R⁶ is C(O)NR⁷R⁷ or C(O)NR⁷R⁸, in conjunction with any of theabove or below embodiments.

In another embodiment of the invention, the compounds, includingstereoisomers, tautomers, solvates, pharmaceutically acceptable salts,derivatives or prodrugs thereof, are defined by general Formula II-A:

wherein

R¹ is C₁₋₈-alkyl, —OC₁₋₈-alkyl, —SC₁₋₈-alkyl, —NHC₁₋₈-alkyl,—N(C₁₋₈-alkyl)₂, C₂₋₈-alkenyl, C₂₋₈-alkynyl or C₃₋₈-cycloalkyl, each ofwhich is optionally substituted with 1-5 substituents of R⁹,

or R¹ is a 3-8 membered monocyclic or 6-12 membered bicyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, saidheteroatoms selected from O, N, or S, wherein said ring system isoptionally substituted independently with 1-5 substituents of R⁹;

each of R² and R³, independently, is H, halo, haloalkyl, NO₂, CN,C₁₋₆-alkoxyl, C₁₋₆-thioalkyl, C₁₋₆-aminoalkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl or C₃₋₆-cycloalkyl, each of the C₁₋₆-alkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl and C₃₋₁₀-cycloalkyl optionally substituted with 1-5substituents of R⁹;

R⁴ is CN, C(O)R⁹, C₁₋₆-alkyl, —OC₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynylor C₃₋₆-cycloalkyl, each of the C₁₋₆-alkyl, —OC₁₋₆-alkyl, C₂₋₆-alkenyl,C₂₋₁₀-alkynyl and C₃₋₆-cycloalkyl optionally substituted with 1-5substituents of R⁹;

each R⁵, independently, is H, halo, haloalkyl, NO₂, CN, OH, C₁₋₆-alkyl,—OC₁₋₆-alkyl, —SC₁₋₆-alkyl, —NHC₁₋₆-alkyl, wherein the C₁₋₆-alkyl ofeach is optionally comprising 1-3 heteroatoms selected from N, O and Sand optionally substituted with 1-5 substituents of R⁹;

R⁶ is C(O)NR⁷R⁷, C(O)NR⁷R⁸, NR⁷C(O)R⁷, NR⁷C(O)R⁸, NR⁷C(O)NR⁷R⁷,NR⁷C(O)NR⁷R⁸, S(O)₂NR⁷R⁷, S(O)₂NR⁷R⁸, NR⁷S(O)₂NR⁷R⁸, NR⁷S(O)₂R⁷ orNR⁷S(O)₂R⁸;

each R⁷, independently, is H, C₁₋₈-alkyl, C₂₋₈-alkenyl, C₂₋₈-alkynyl orC₃₋₈-cycloalkyl, each of the C₁₋₈-alkyl, C₂₋₈-alkenyl, C₂₋₈-alkynyl andC₃-cycloalkyl optionally comprising 1-4 heteroatoms selected from N, Oand S and optionally substituted with one or more substituents of NR⁸R⁹,NR⁹R⁹, OR^(B), SR⁸, OR⁹, SR⁹, C(O)R⁸, OC(O)R⁸, COOR^(S), C(O)R⁹,OC(O)R⁹, COOR⁹, C(O)NR⁸R⁹, C(O)NR⁹R⁹, NR⁹C(O)R⁸, NR⁹C(O)R⁹,NR⁹C(O)NR⁸R⁹, NR⁹C(O)NR⁹R⁹, NR⁹(COOR⁸), NR⁹(COOR⁹), OC(O)NR⁸R⁹,OC(O)NR⁹R⁹, S(O)₂R⁸, S(O)₂NR⁸R⁹, S(O)₂R⁹, S(O)₂NR⁹R⁹, NR⁹S(O)₂NR⁸R⁹,NR⁹S(O)₂NR⁹R⁹, NR⁹S(O)₂R⁸, NR⁹S(O)₂R⁹, R⁸ or R⁹;

R⁸ is a partially or fully saturated or fully unsaturated 3-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, andwherein each ring of said ring system is optionally substitutedindependently with 1-5 substituents of R⁹, oxo, NR⁹R⁹, OR⁹, SR⁹, C(O)R⁹,COOR⁹, C(O)NR⁹R⁹, NR⁹C(O)R⁹, NR⁹C(O)NR⁹R⁹, OC(O)NR⁹R⁹, S(O)₂R⁹,S(O)₂NR⁹R⁹, NR⁹S(O)₂R⁹, or a partially or fully saturated or unsaturated5-6 membered ring of carbon atoms optionally including 1-3 heteroatomsselected from O, N, or S, and optionally substituted independently with1-3 substituents of R⁹;

alternatively, R⁷ and R⁸ taken together form a saturated or partially orfully unsaturated 5-6 membered monocyclic or 7-10 membered bicyclic ringof carbon atoms optionally including 1-3 heteroatoms selected from O, N,or S, and the ring optionally substituted independently with 1-5substituents of R⁹;

R⁹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, oxo, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl,C₁₋₁₀-thioalkoxyl, —SO₂C₁₋₁₀-alkyl or a saturated or partially or fullyunsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14membered tricyclic ring system, said ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms ifbicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selectedfrom O, N, or S, wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and each ring ofsaid ring system is optionally substituted independently with 1-3substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl; and

X is O or S.

In another embodiment, the invention provides compounds of Formula IIand II-A wherein each of the various embodiments above for A, R¹, R²,R³, R₄, R₆, R₇, R₈ and n for compounds of Formula I can be applied tocompounds of Formula II and II-A, in conjunction with any of the aboveor below embodiments.

In another embodiment, the invention provides compounds of Formulas Iand II, or a pharmaceutically acceptable salt thereof, selected from

DEFINITIONS

The following definitions should assist in understanding the inventiondescribed herein.

The term “comprising” is meant to be open ended, including the indicatedcomponent(s), but not excluding other elements.

The term “C_(α-β)alkyl”, when used either alone or within other termssuch as “haloalkyl” and “alkylamino”, embraces linear or branchedradicals having α to β number of carbon atoms (such as C₁-C₁₀). Examplesof such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl and the like.The term “alkylenyl” embraces bridging divalent alkyl radicals such asmethylenyl and ethylenyl.

The term “alkenyl”, when used alone or in combination, embraces linearor branched radicals having at least one carbon-carbon double bond in amoiety having between two and ten carbon atoms. Examples of alkenylradicals include, without limitation, ethenyl, propenyl, allyl,propenyl, butenyl and 4-methylbutenyl. The terms “alkenyl” and “loweralkenyl”, embrace radicals having “cis” and “trans” orientations, oralternatively, “E” and “Z” orientations, as appreciated by those ofordinary skill in the art.

The term “alkynyl”, when used alone or in combination, denotes linear orbranched radicals having at least one carbon-carbon triple bond andhaving two to ten carbon atoms. Examples of such radicals include,without limitation, ethynyl, propynyl (propargyl), butynyl, and thelike.

The term “alkoxy” or “alkoxyl”, when used alone or in combination,embraces linear or branched oxygen-containing radicals each having alkylportions of one or more carbon atoms. Examples of such radicals includemethoxy, ethoxy, propoxy, butoxy and tert-butoxy. Alkoxy radicals may befurther substituted with one or more halo atoms, such as fluoro, chloroor bromo, to provide “haloalkoxy” radicals. Examples of such radicalsinclude fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy,fluoroethoxy and fluoropropoxy.

The term “aryl”, when used alone or in combination, means a carbocyclicaromatic moiety containing one, two or even three rings wherein suchrings may be attached together in a fused manner. Every ring of an“aryl” ring system need not be aromatic, and the ring(s) fused to thearomatic ring may be partially or fully unsaturated and include one ormore heteroatoms selected from nitrogen, oxygen and sulfur. Thus, theterm “aryl” embraces aromatic radicals such as phenyl, naphthyl,indenyl, tetrahydronaphthyl, dihydrobenzafuranyl, anthracenyl, indanyl,benzodioxazinyl, and the like. Unless otherwise specified, the “aryl”group may be substituted, such as with 1 to 5 substituents includinglower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy and loweralkylamino, and the like. Phenyl substituted with —O—CH₂—O— or—O—CH₂—CH₂—O— forms an aryl benzodioxolyl substituent.

The term “carbocyclic”, also referred to herein as “cycloalkyl”, whenused alone or in combination, means a partially or fully saturated ringmoiety containing one (“monocyclic”), two (“bicyclic”) or even three(“tricyclic”) rings wherein such rings may be attached together in afused manner and formed from carbon atoms. Examples of saturatedcarbocyclic radicals include saturated 3 to 6-membered monocyclic groupssuch as cyclopropane, cyclobutane, cyclopentane and cyclohexane andpartially saturated monocyclic groups such as cyclopentene, cyclohexeneor cyclohexadiene. The partially saturated groups are also encompassedin the term “cycloalkenyl” as defined below.

The terms “ring” and “ring system” refer to a ring comprising thedelineated number of atoms, the atoms being carbon or, where indicated,a heteroatom such as nitrogen, oxygen or sulfur. Where the number ofatoms is not delineated, such as a “monocyclic ring system” or a“bicyclic ring system”, the numbers of atoms are 3-8 for a monocyclicand 6-12 for a bicyclic ring. The ring itself, as well as anysubstitutents thereon, may be attached at any atom that allows a stablecompound to be formed. The term “nonaromatic” ring or ring system refersto the fact that the ring, at the point of attachment, is nonaromatic.

The terms “partially or fully saturated or unsaturated” and “saturatedor partially or fully unsaturated” with respect to each individual ring,refer to the ring either as fully aromatic (fully unsaturated),partially aromatic (or partially saturated) or fully saturated(containing no double or triple bonds therein). If not specified assuch, then it is contemplated that each ring (monocyclic) in a ringsystem (if bicyclic or tricyclic) may either be fully aromatic,partially aromatic or fully saturated, and optionally substituted withup to 5 substituents.

Thus, the term “a 3-8 membered monocyclic or 6-12 membered bicyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, saidheteroatoms selected from O, N, or S, wherein said ring system isoptionally substituted” refers to a single ring or multiple ring systemcomprising the delineated number of atoms, the atoms being carbon or,where indicated, a heteroatom such as nitrogen (N), oxygen (O) or sulfur(S). Where the number of atoms is not delineated, such as a “monocyclicring system” or a “bicyclic ring system”, the numbers of atoms are 3-8for a monocyclic and 6-12 for a bicyclic ring. The ring or ring systemmay contain substitutents thereon, attached at any atom that allows astable compound to be formed.

The term “cycloalkenyl”, when used alone or in combination, means apartially or fully saturated cycloalkyl containing one, two or eventhree rings in a structure having at least one carbon-carbon double bondin the structure. Examples of cycloalkenyl groups include C₃-C₆ rings,such as compounds including, without limitation, cyclopropene,cyclobutene, cyclopentene and cyclohexene. The term also includescarbocyclic groups having two or more carbon-carbon double bonds such as“cycloalkyldienyl” compounds. Examples of cycloalkyldienyl groupsinclude, without limitation, cyclopentadiene and cycloheptadiene.

The term “halo”, when used alone or in combination, means halogens suchas fluorine, chlorine, bromine or iodine atoms.

The term “haloalkyl”, when used alone or in combination, embracesradicals wherein any one or more of the alkyl carbon atoms issubstituted with halo as defined above. For example, this term includesmonohaloalkyl, dihaloalkyl and polyhaloalkyl radicals such as aperhaloalkyl. A monohaloalkyl radical, for example, may have either aniodo, bromo, chloro or fluoro atom within the radical. Dihalo andpolyhaloalkyl radicals may have two or more of the same halo atoms or acombination of different halo radicals. Examples of haloalkyl radicalsinclude fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl,difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,difluoropropyl, dichloroethyl and dichloropropyl. “Perfluoroalkyl”, asused herein, refers to alkyl radicals having all hydrogen atoms replacedwith fluoro atoms. Examples include trifluoromethyl andpentafluoroethyl.

The term “heteroaryl”, as used herein, either alone or in combination,means a fully unsaturated (aromatic) ring moiety formed from carbonatoms and having one or more heteroatoms selected from nitrogen, oxygenand sulfur. The ring moiety or ring system may contain one(“monocyclic”), two (“bicyclic”) or even three (“tricyclic”) ringswherein such rings are attached together in a fused manner. Every ringof a “heteroaryl” ring system need not be aromatic, and the ring(s)fused thereto (to the heteroaromatic ring) may be partially or fullysaturated and optionally include one or more heteroatoms selected fromnitrogen, oxygen and sulfur. The term “heteroaryl” does not includerings having ring members of —O—O—, —O—S— or —S—S—.

Examples of heteroaryl radicals, include unsaturated 5- to 6-memberedheteromonocyclyl groups containing 1 to 4 nitrogen atoms, including forexample, pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl,4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g.,4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl] andtetrazole; unsaturated 7- to 10-membered heterobicyclyl groupscontaining 1 to 4 nitrogen atoms, including for example, quinolinyl,isoquinolinyl, quinazolinyl, isoquinazolinyl, aza-quinazolinyl, and thelike; unsaturated 5- to 6-membered heteromonocyclic group containing anoxygen atom, for example, pyranyl, 2-furyl, 3-furyl, benzofuryl, etc.;unsaturated 5 to 6-membered heteromonocyclic group containing a sulfuratom, for example, a thienyl (also referred to as thiophenyl) such as2-thienyl, 3-thienyl, benzothienyl, etc.; unsaturated 5- to 6-memberedheteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [e.g.,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl]; unsaturated 5to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and1 to 3 nitrogen atoms, for example, thiazolyl, isothiazolyl,thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl].

The term “heteroaryl” also embraces bicyclic radicals wherein 5- or6-membered heteroaryl radicals are fused/condensed with aryl radicals orunsaturated condensed heterocyclic groups containing 1 to 5 nitrogenatoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl,quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl[e.g., tetrazolo[1,5-b]pyridazinyl]; unsaturated condensed heterocyclicgroup containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.benzoxazolyl, benzoxadiazolyl]; unsaturated condensed heterocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g.,benzothiazolyl, benzothiadiazolyl]; and saturated, partially unsaturatedand unsaturated condensed heterocyclic group containing 1 to 2 oxygen orsulfur atoms [e.g. benzofuryl, benzothienyl,2,3-dihydro-benzo[1,4]dioxinyl and dihydrobenzofuryl]. Examples ofheterocyclic radicals include five to ten membered fused or unfusedradicals.

The term “heterocyclic”, when used alone or in combination, means apartially or fully saturated ring moiety containing one, two or eventhree rings wherein such rings may be attached together in a fusedmanner, formed from carbon atoms and including one or more heteroatomsselected from N, O or S. Examples of heterocyclic radicals includesaturated 3 to 6-membered heteromonocyclic groups containing 1 to 4nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl, piperidinyl,pyrrolinyl, piperazinyl]; saturated 3 to 6-membered heteromonocyclicgroup containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.morpholinyl]; saturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g.,thiazolidinyl]. Examples of partially saturated heterocyclyl radicalsinclude dihydrothienyl, dihydropyranyl, dihydrofuryl anddihydrothiazolyl.

Examples of partially saturated and saturated heterocyclyl include,without limitation, pyrrolidinyl, imidazolidinyl, piperidinyl,pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl,thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl,indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl,isochromanyl, chromanyl, 1,2-dihydroquinolyl,1,2,3,4-tetrahydro-isoquinolyl, 1,2,3,4-tetrahydro-quinolyl,2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl,5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl,3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl,2,3-dihydro-1H-1λ′-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuryland dihydrothiazolyl, and the like.

The term “alkylamino” includes “N-alkylamino” where amino radicals areindependently substituted with one alkyl radical. Preferred alkylaminoradicals are “lower alkylamino” radicals having one to six carbon atoms.Even more preferred are lower alkylamino radicals having one to threecarbon atoms. Examples of such lower alkylamino radicals includeN-methylamino, and N-ethylamino, N-propylamino, N-isopropylamino and thelike.

The term “dialkylamino” includes “N,N-dialkylamino” where amino radicalsare independently substituted with two alkyl radicals. Preferredalkylamino radicals are “lower alkylamino” radicals having one to sixcarbon atoms. Even more preferred are lower alkylamino radicals havingone to three carbon atoms. Examples of such lower alkylamino radicalsinclude N,N-dimethylamino, N,N-diethylamino, and the like.

The term “aminocarbonyl” denotes an amide group of the formula—C(═O)NH₂.

The terms “alkylthio” and “thioalkoxyl” embrace radicals containing alinear or branched alkyl radical, of one to ten carbon atoms, attachedto a divalent sulfur atom. An example of “alkylthio” is methylthio,(CH₃S—).

The term “Formula I” includes any sub formulas, such as Formulas I-B andI-C.

The term “pharmaceutically-acceptable” when used with reference to acompound of Formulas I, I-B, I-C and II is intended to refer to a formof the compound that is safe for administration. For example, a freebase, a salt form, a solvate, a hydrate, a prodrug or derivative form ofa compound of Formula I, I-B, I-C or of Formula II, which has beenapproved for mammalian use, via oral ingestion or any other route ofadministration, by a governing body or regulatory agency, such as theFood and Drug Administration (FDA) of the United States, ispharmaceutically acceptable.

Included in the compounds of Formulas I, I-B, I-C and II are thepharmaceutically acceptable salt forms of the free-base compounds. Theterm “pharmaceutically-acceptable salts” embraces salts, commonly usedto form alkali metal salts and to form addition salts of free acids orfree bases, which have been approved by a regulatory agency. Asappreciated by those of ordinary skill in the art, salts may be formedfrom ionic associations, charge-charge interactions, covalent bonding,complexation, coordination, etc. The nature of the salt is not critical,provided that it is pharmaceutically acceptable.

Suitable pharmaceutically acceptable acid addition salts of compounds ofFormulas I, I-B, I-C and II may be prepared from an inorganic acid orfrom an organic acid. Examples of such inorganic acids are hydrochloric,hydrobromic, hydroiodic, hydrofluoric, nitric, carbonic, sulfonic,sulfuric and phosphoric acid. Appropriate organic acids may be selectedfrom aliphatic, cycloaliphatic, aromatic, arylaliphatic, heterocyclic,carboxylic and sulfonic classes of organic acids, examples of whichinclude, without limitation, formic, acetic, adipic, butyric, propionic,succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic,glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic,anthranilic, mesylic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic(pamoic), methanesulfonic, ethanesulfonic, ethanedisulfonic,benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic,sulfanilic, cyclohexylaminosulfonic, camphoric, camphorsulfonic,digluconic, cyclopentanepropionic, dodecylsulfonic, glucoheptanoic,glycerophosphonic, heptanoic, hexanoic, 2-hydroxy-ethanesulfonic,nicotinic, 2-naphthalenesulfonic, oxalic, palmoic, pectinic,persulfuric, 2-phenylpropionic, picric, pivalic propionic, succinic,thiocyanic, undecanoic, stearic, algenic, β-hydroxybutyric, salicylic,galactaric and galacturonic acid. Suitable pharmaceutically-acceptablebase addition salts of compounds of Formulas I and II include metallicsalts, such as salts made from aluminum, calcium, lithium, magnesium,potassium, sodium and zinc, or salts made from organic bases including,without limitation, primary, secondary and tertiary amines, substitutedamines including cyclic amines, such as caffeine, arginine,diethylamine, N-ethyl piperidine, histidine, glucamine, isopropylamine,lysine, morpholine, N-ethyl morpholine, piperazine, piperidine,triethylamine, disopropylethylamine and trimethylamine. All of thesesalts may be prepared by conventional means from the correspondingcompound of the invention by reacting, for example, the appropriate acidor base with the compound of Formulas I, I-B, I-C and II.

Also, the basic nitrogen-containing groups can be quaternized with suchagents as lower alkyl halides, such as methyl, ethyl, propyl, and butylchloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl,dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl,myristyl and stearyl chlorides, bromides and iodides, aralkyl halideslike benzyl and phenethyl bromides, and others. Water or oil-soluble ordispersible products are thereby obtained.

Examples of acids that may be employed to form pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid (HCl), hydrobromic acid (HBr), citric acid, sulphuricacid and phosphoric acid and such organic acids as oxalic acid, stearicand, salicylic acid, pamoic acid, gluconic acid, ethanesulfonic acid,methanesulfonic acid (MSA), benzenesulfonic acid (BSA), toluenesulfonicacid, tartaric acid, fumaric acid, medronic acid, napsylic acid, maleicacid, succinic acid and citric acid. Other examples include salts withalkali metals or alkaline earth metals such as sodium, potassium,calcium or magnesium, or with organic bases.

Additional examples of such salts can be found in Berge et al., J.Pharm. Sci., 66, 1 (1977). Conventional methods may be used to form thesalts. For example, a phosphate salt of a compound of the invention maybe made by combining the desired compound free base in a desiredsolvent, or combination of solvents, with phosphoric acid in a desiredstoichiometric amount, at a desired temperature, typically under heat(depending upon the boiling point of the solvent). The salt can beprecipitated upon cooling (slow or fast) and may crystallize (i.e., ifcrystalline in nature), as appreciated by those of ordinary skill in theart. Further, hemi-, mono-, di, tri- and poly-salt forms of thecompounds of the present invention are also contemplated herein.Similarly, hemi-, mono-, di, tri- and poly-hydrated forms of thecompounds, salts and derivatives thereof, are also contemplated herein.

The term “derivative” is broadly construed herein, and intended toencompass any salt of a compound of this invention, any ester of acompound of this invention, or any other compound, which uponadministration to a patient is capable of providing (directly orindirectly) a compound of this invention, or a metabolite or residuethereof, characterized by the ability to the ability to modulate akinase enzyme.

The term “pharmaceutically-acceptable derivative” as used herein,denotes a derivative, which is pharmaceutically acceptable.

The term “prodrug”, as used herein, denotes a compound which uponadministration to a subject or patient is capable of providing (directlyor indirectly) a compound of this invention. Examples of prodrugs wouldinclude esterified or hydroxylated compounds where the ester or hydroxylgroups would cleave in vivo, such as in the gut, to produce a compoundaccording to Formulas I, I-B, I-C and II. A “pharmaceutically-acceptableprodrug” as used herein, denotes a prodrug, which is pharmaceuticallyacceptable. Pharmaceutically acceptable modifications to the compoundsof Formula I are readily appreciated by those of ordinary skill in theart.

The compound(s) of Formulas I, I-B, I-C and II may be used to treat asubject by administering the compound(s) as a pharmaceuticalcomposition. To this end, the compound(s) can be combined with one ormore carriers, diluents or adjuvants to form a suitable composition,which is described in more detail herein.

The term “excipient”, as used herein, denotes any pharmaceuticallyacceptable additive, carrier, adjuvant, or other suitable ingredient,other than the active pharmaceutical ingredient (API), which istypically included for formulation and/or administration purposes.“Diluent” and “adjuvant” are defined hereinafter.

The terms “treat”, “treating,” “treatment,” and “therapy” as used hereinrefer to therapy, including without limitation, curative therapy,prophylactic therapy, and preventative therapy. Prophylactic treatmentgenerally constitutes either preventing the onset of disordersaltogether or delaying the onset of a pre-clinically evident stage ofdisorders in individuals.

The phrase “effective dosage amount” is intended to quantify the amountof each agent, which will achieve the goal of improvement in disorderseverity and the frequency of incidence over treatment of each agent byitself, while avoiding adverse side effects typically associated withalternative therapies.

The term “leaving groups” (also denoted as “LG”) generally refer togroups that are displaceable by a nucleophile. Such leaving groups areknown in the art. Examples of leaving groups include, but are notlimited to, halides (e.g., I, Br, F, Cl), sulfonates (e.g., mesylate,tosylate), sulfides (e.g., SCH₃), N-hydroxsuccinimide,N-hydroxybenzotriazole, and the like. Nucleophiles are species that arecapable of attacking a molecule at the point of attachment of theleaving group causing displacement of the leaving group. Nucleophilesare known in the art. Examples of nucleophilic groups include, but arenot limited to, amines, thiols, alcohols, Grignard reagents, anionicspecies (e.g., alkoxides, amides, carbanions) and the like.

General Synthetic Procedures

The present invention further comprises procedures for the preparationof compounds of Formulas I, I-B, I-C and II. The compounds of FormulasI, I-B, I-C and II can be synthesized according to the proceduresdescribed in the following Scheme 1 (corresponding to general Method A,respectively), wherein the substituents are as defined for Formulas I,I-B, I-C and II, above, except where further noted. The syntheticmethods described below are merely exemplary, and the compounds of theinvention may also be synthesized by alternate routes as appreciated bypersons of ordinary skill in the art.

The following list of abbreviations used throughout the specificationrepresent the following and should assist in understanding theinvention:

-   ACN, MeCN—acetonitrile-   BSA—bovine serum albumin-   BOP—benzotriazol-1-yl-oxy hexafluorophosphate-   Br₂—bromine-   CDI—carbonyldiimidazole-   Cs₂CO₃—cesium carbonate-   CHCl₃—chloroform-   CH₂Cl₂, DCM—dichloromethane, methylene chloride-   DCC—dicyclohexylcarbodiimide-   DIC—1,3-diisopropylcarbodiimide-   DIEA, DIPEA—diisopropylethylamine-   DME—dimethoxyethane-   DMF—dimethylformamide-   DMAP—dimethylaminopyridine-   DMSO—dimethylsulfoxide-   EDC—1-(3-dimethylaminopropyl)-3-ethylcarbodiimide-   Et₂O—diethyl ether-   EtOAc—ethyl acetate-   G, g, gm—gram-   h, hr—hour-   H₂—hydrogen-   H₂O—water-   HATU—O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate-   HBr—hydrobromic acid-   HCl—hydrochloric acid-   HOBt—1-hydroxybenzotriazole hydrate-   HOAc—acetic acid-   HPLC—high pressure liquid chromatography-   IPA, IpOH—isopropyl alcohol-   K₂CO₃—potassium carbonate-   LG—leaving group-   MgSO₄—magnesium sulfate-   MS—mass spectrum-   MeOH—methanol-   N₂—nitrogen-   NaCNBH₃—sodium cyanoborohydride-   Na₂CO₃—sodium carbonate-   NaHCO₃—sodium bicarbonate-   NaH—sodium hydride-   NaOCH₃—sodium methoxide-   NaOH—sodium hydroxide-   Na₂SO₄—sodium sulfate-   NBS—N-bromosuccinimide-   NH₄Cl—ammonium chloride-   NH₄OH—ammonium hydroxide-   NMP—N-methylpyrrolidinone-   P(t-bu)₃—tri(tert-butyl)phosphine-   PBS—phospate buffered saline-   Pd/C—palladium on carbon-   Pd(PPh₃)₄—palladium(0)triphenylphosphine tetrakis-   Pd(dppf)Cl₂—palladium(1,1-bisdiphenylphosphinoferrocene) II chloride-   Pd(OAc)₂—palladium acetate-   PyBop—benzotriazol-1-yl-oxy-tripyrrolidino-phosphonium    hexafluorophosphate-   RT, rt—room temperature-   TBTU—O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium    tetrafluoroborate-   TEA, Et₃N—triethylamine-   TFA—trifluoroacetic acid-   THF—tetrahydrofuran-   UV—ultraviolet light

Phenyl-substituted pyridazino-pyridinones 12, (Formula I; the ring shownas a phenyl ring in scheme 1 is generally referred to herein throughoutthe specification as the “B” ring) may be made by the method generallydescribed in Scheme 1, also designated herein as Method A. As shown, adesirable R² substituted dibromo pyridazinone 1 may be reacted with4-methoxybenzylchloride in the presence of tetrabutylammonium bromideand a suitable base, such as a carbonate base, for instance potassiumcarbonate as shown, to afford the alkylated adduct 2. One bromide ofcompound 2 may be selectively aminated with methyl amine under suitablereaction conditions such as toluene and heat as shown, to produce theamino methylpyridazinone intermediate 3. The other bromide ofpyridazinone 3 can be converted to the corresponding Weinreb amide 4under conditions shown above, and subsequently reduced with thecorresponding aldehyde 5 with a suitable reducing agent, such as LAH asshown. Aldehyde 5 may be converted to the corresponding ester 6 usingthe appropriate malonate as shown. Note that this method affordscompounds where R⁴ is methyl. Similar procedures may be employed toproduce compounds of Formulas I and II wherein R⁴ is other alkylmoieties, such as ethyl, propyl, butyl, isopropyl, pentyl and the like.

The para-methoxybenzyl protecting group of intermediate 6 can be removedwith an acid, such as TFA, followed by conversion of the carbonyl oncompound 6 to the corresponding chloride 7 using conventional methods,such as phosphorus oxychloride under suitable conditions. The chlorideof intermediate 7 can then be reacted with an aromatic boronic acid 8 toinstall a desired aromatic R¹ group to afford intermediate 9, underSuzuki or Suzuki-like reaction conditions, which are generally known inthe art, and which are briefly described herein below. Note that theSuzuki or like reaction generally employs use of a base, of which thebase also serves to hydrolyze the ester in 7 to the corresponding acid9. The acid of compound 9 can be converted to the corresponding bromide10 using conventional methods, such as with a suitable brominating agentsuch as NBS under suitable conditions, as those shown above. The bromineadduct 10 can be subjected to suitable Suzuki Coupling conditions, suchas those shown in scheme 1, with a desired boronic ester intermediate 11to afford the desired substituted pyridazino-pyridinone 12.

The boronic ester intermediates 8 and 11 may be prepared by methodsdescribed in the following references: (1) PCT Int. Patent Appl. No. WO2005073189, titled “Preparation of fused heteroaryl derivatives as p38kinase inhibitors” or (2) PCT Int. Patent Appl. No. WO 2006094187,titled “Preparation of phthalazine, aza- and diaza-phthalazine compoundsas protein kinase, especially p38 kinase, inhibitors for treatinginflammation and related conditions”, both publications of which arehereby incorporated herein by reference in their entirety.

The Suzuki method is a reaction using a borane reagent, such as adioxaborolane intermediate 11 (also described in scheme 3 below as aborane B-A intermediate 8), and a suitable leaving group containingreagent, such as the Br-pyridazino-pyridinone 10 (Br is a suitablehalogen leaving group “LG”). As appreciated to one of ordinary skill inthe art, Suzuki reactions also utilize a palladium catalyst. Suitablepalladium catalysts include Pd(PPh₃)₄, Pd(OAc)₂ or Pd(dppf)Cl₂. Where LGis a halide, the halide may be an iodide, a bromide or even a chloride(chloro-pyridyl or chloro-picolinyl B rings undergo Suzuki reactions inthe presence of Pd(OAc)₂). Other LGs are also suitable. For example,Suzuki couplings are known to occur with a sulfonate, such astrifluoromethanesulfonate, as the leaving group.

The Suzuki reaction conditions may vary. For example, Suzuki reactionsare generally run in the presence of a suitable base such as a carbonatebase, bicarbonate or an acetate base, in a suitable solvent such astoluene, dioxane, 2-butanol, acetonitrile, DMF or an aqueous-organicsolvent combination or a biphasic system of solvents. Further, thereaction may require heat depending upon the particularpyradazino-pyridinone 10 and/or boronic acid or ester 11, as appreciatedby those skilled in the art. In addition, where the B ring is anaromatic moiety, such as phenyl, the reaction may be complete in a shortperiod of time with heat.

Other methods of installing the boronate on a desired aromatic ring areknown. For example metal coupling chemistry, such Stille, Kumada,Negishi coupling methods, and the like, may be employed to thepyridazino-pyridinone cores 7 or 10 to prepare desired cyclicB-ring—substituted intermediates.

The general method shown in scheme 1 to prepare compounds of Formula Iof the invention may also be employed to prepare compounds of Formula IIwherein one of A¹⁻³ is N and remaining of A¹⁻³ are CR⁵.

Alternatively, substituted pyridazino-pyridinones 16, (where each ofA¹⁻³ independently, of the B ring may be either N or CR⁵ and R⁶ as shownis an amide linker) may be made by the method generally described inScheme 2. In this method, bromo pyridazino-pyridinones 13 can be reactedwith a desired B-ring substituted boronic acid 14 in the presence of asuitable palladium catalyst, such as those shown or described in schemes1 above, to provide the pyridazino-pyridinone intermediate 15. The acidgroup of 15 can be activated to the corresponding acid chloride usingthionyl chloride, which can then be reacted with a desirably substitutedamine to produce final compounds 16 of Formula I. In such a manner, theavailable carboxylic acid of 15 allows one to, in a single reactionstep, vary the substituents of R⁷, R⁸ and/or R⁹ groups, which aregenerally attached therefrom.

For example, the acid of compounds 15, or 14, can be activated tocoupling via various well known acid LG's, such as conversion to thecorresponding acid chloride species as shown, followed by treatment witha suitable primary or secondary nucleophilic moiety, such as anappropriately substituted amine as shown, to afford the correspondingdesired pyridazino-pyridinone product 16.

Substituted pyridazino-pyridinones 22 (where each of A¹⁻³,independently, of the B ring is CR⁵) may be made by the method generallydescribed in Scheme 3. In this method, the nitro group ofchloro-bromo-nitrobenzene 17 can be reduced using conventional methods,such as by hydrogenation, to afford the free amine 18 Amine 18 can befirst protected with a suitable protecting group such as BOC, and thenconverted to the corresponding boronate 19 (as shown). Boronateintermediate 19 can be reacted with pyrazolo-pyridinone 13 undersuitable Suzuki or like coupling conditions, such as those shown aboveand in scheme 1, to afford the coupled intermediate 20. Boc amine 20 canbe converted to the corresponding iodide 21 under conventionalconditions, such as by first removing the BOC group and converting theresulting amine to iodide using known reagents, such as those shownabove. Iodide 21 can be converted to the corresponding cyano group 22under conventional conditions, such as those described above. The cyanogroup is regarded as a synthon for a carboxylic acid group, to which itmay be converted using known reaction conditions, the acid of which canthen be functionalized according to scheme 2 above.

Substituted pyridazino-pyridinethiones 24 may be made by the methodgenerally described in Scheme 4. In this method, the carbonyl of thebromo-pyridazino-pyridinone intermediate 13 can be converted to thecorresponding thio-carbonyl 23 using conventional methods, such as withLawessen's Reagent under suitable conditions. Thio-carbonyl 23 can bereacted with a boronate 11 (as shown in Method A, scheme 1) undersuitable Suzuki or Suzuki-like coupling conditions to afford the coupledadduct 24.

Various other linker R⁶ groups are within the scope of the presentinvention. Such other linkers may be made using the general methodsdescribed in scheme 5 below. As illustrated in scheme 5, desirable R⁷and R⁸ groups are shown as a ring designated as ring A. However, thepresent invention is not so limited, and it is intended that what isdepicted as “ring A” in scheme 5 should be read to also include noncyclic moieties attached to linker R⁶, as described in Formulas I, I-A,I-B, I-C and II herein.

The B ring, as illustrated in scheme 5, is substituted by a linker groupR⁶. The R⁶ linker group, including an amino, a carboxyl, a sulfonyl, anamido or a urea linker, as defined herein in Formulas I, I-A, I-B andI-C, and Formula II, connect various substitutions, including R⁷non-cyclic moieties or R⁷ and R⁸ cyclic rings (generally designated andreferred to in Scheme 5, and throughout the specification, as the “A”group or “A” ring) to the “B” ring. This linker may be attached byvarious coupling methods as described in Scheme 5. Each of the ninesub-schemes, numbered 1-9 above and described below, utilize thefollowing meanings for (R)_(n), X, Nu⁻, E⁺ and m: (R)_(n) refers to nnumber of R⁹ substitutions wherein n is an integer from 0-5; X refersgenerally to a “leaving group” (also referred to herein as “LG”) such asa halide (bromine, chlorine, iodine or fluorine), alkylsulfonate andother known groups (also see definitions herein); Nu⁻ refers generallyto a nucleophilic species such as a primary or secondary amine, anoxygen, a sulfur or a anionic carbon species—examples of nucleophilesinclude, without limitation, amines, hydroxides, alkoxides and the like;E⁺ refers generally to an electrophilic species, such as the carbon atomof a carbonyl, which is susceptible to nucleophilic attack or readilyeliminates—examples of suitable electrophilic carbonyl species include,without limitation, acid halides, mixed anhydrides, aldehydes,carbamoyl-chlorides, sulfonyl chlorides, acids activated with activatingreagents such as TBTU, HBTU, HATU, HOBT, BOP, PyBOP and carbodiimides(DCC, EDC, CDI and the like), and other electrophilic species includinghalides, isocyanates, daizonium ions and the like; and m is either 0 or1.

The coupling of ring B to A, as shown as products in sub-schemes 1-9,can be brought about using various conventional methods to link ring Band A together. For example, an amide or a sulfonamide linkage, as shownin sub-schemes 2 and 4, and 7 and 9 where the Nu− is an amine,respectively, can be made utilizing an amine on either the B or A groupsand an acid chloride or sulfonyl chloride on the other of either the Bor A groups. The reaction proceeds generally in the presence of asuitable solvent and/or base. Suitable solvents include, withoutlimitation, generally non-nucleophilic, anhydrous solvents such astoluene, CH₂Cl₂, THF, DMF, DMSO, N,N-dimethylacetamide and the like,including solvent combinations thereof. The solvent may range inpolarity, as appreciated by those skilled in the art. Suitable basesinclude, for example, tertiary amine bases such as DIEA, TEA, carbonatebases such as Na₂CO₃, K₂CO₃, Cs₂CO₃, hydrides such as NaH, KH,borohydrides, cyanoborohydrides and the like, alkoxides such as NaOCH₃,and the like. The base itself may also serve as a solvent. The reactionmay optionally be run neat, i.e., without any base and/or solvent. Thesecoupling reactions are generally fast and conversion occurs typically inambient conditions. However, depending upon the particular substrate,such reactions may require heat, as appreciated by those skilled in theart.

Similarly, carbamates as illustrated in sub-schemes 5 and 1 where Nu− isan amine, anhydrides as illustrated in sub-scheme 1 where Nu− is anoxygen, reverse amides as generally illustrated in sub-scheme 8 whereNu− is an amine and E+ is an acid chloride, ureas as illustrated insub-scheme 3, thioamides and thioureas where the respective carbonyloxygen is a sulfur, thiocarbamates where the respective carbonyl oxygenand/or carbamate oxygen is a sulfur, and the like. While the abovemethods are so described, they are not exhaustive, and other methods forlinking groups A and B together may be utilized as appreciated by thoseskilled in the art.

Although sub-schemes 1-9 are illustrated as having the nucleophilic andelectrophilic coupling groups, such as the amino group and acid chloridegroups illustrated in sub-scheme 2, directly attached to the substrate,either the A group or B ring, in question, the invention is not solimited. It is contemplated herein that these nucleophilic and/orelectrophilic coupling groups may be tethered from their respectivering. For example, the amine group on the B ring, and/or the acid halidegroup on the A group or ring, as illustrated in sub-scheme 2, may beremoved from direct attachment to the ring by a one or more atom spacer,such as by a methylene, ethylene spacer or the like. As appreciated bythose skilled in the art, such spacer may or may not affect the couplingreactions described above, and accordingly, such reaction conditions mayneed to be modified to effect the desired transformation.

The coupling methods described in sub-schemes 1-9 of scheme 6 are alsoapplicable for coupling desired A groups or rings to desiredpyrazolo-pyridinone-B ring intermediates, such as to substituted B ringcarboxylic acids to synthesize desired compounds of Formulas I, I-A, I-Band I-C and Formula II. For example, a desirably substitutedpyridazino-pyridinone-benzoic acid maybe reacted with a desirablysubstituted primary or secondary amine, such as an NHR⁷R⁷ or NHR⁷R⁸group in the presence of a suitable solvent and a known couplingreagent, such as TBTU, HATU, CDI or others, to prepare the desired A-Bamide bond, and the final compound of Formulas I or I-B.

Note that the B-A moiety is connected through a linker “L”. “L” may beany linker generally defined by the R⁶ groups in Formulas I, I-A, I-Band I-C, and Formula II, and particularly, it includes, withoutlimitation, an amide, a urea, a thiourea, a thioamide, a sulfonamide andthe like, allowing for spacer atoms either between ring B and L and/orbetween ring or group A and L, as described in Scheme 5 above.

To enhance the understanding and appreciation of the present invention,the following specific examples (starting reagents, intermediates andcompounds of Formulas I, I-A, I-B and I-C, and II) and methods of makingcompounds of the invention are set forth. It should be appreciated thatthe above general methods and specific examples below are merely forillustrative purposes only and are not to be construed as limiting thescope of this invention in any manner. The following analytical methodswere used to purify and/or characterize the compounds, andintermediates, described in the examples below.

Analytical Methods:

Unless otherwise indicated, all HPLC analyses were run on a AgilentModel 1100 system with an Agilent Technologies Zorbax SB-C₈(5μ) reversephase column (4.6×150 mm; Part no. 883975-906) run at 30° C. with a flowrate of about 1.50 mL/min. The mobile phase used solvent A (H₂O/0.1%TFA) and solvent B (ACN/0.1% TFA) with a 11 min gradient from 5% to 100%ACN. The gradient was followed by a 2 min. return to 5% ACN and about a2.5 min. re-equilibration (flush).

LC-MS Method:

Samples were run on an Agilent model-1100 LC-MSD system with anPhenomenex Synergi MAX-RP (4.0μ) reverse phase column (2×50 mm) at 40°C. The flow rate was constant and ranged from about 0.75 mL/min to about1.0 mL/min.

The mobile phase used a mixture of solvent A (H₂O/0.1% TFA) and solventB (ACN/0.1% TFA) with a 5 min time period for a gradient from 10% to100% solvent B. The gradient was followed by a 0.5 min period to returnto 10% solvent B and a 1.5 min 10% solvent B re-equilibration (flush) ofthe column.

Preparative HPLC Method:

Where indicated, compounds of interest were purified via reverse phaseHPLC using a Gilson workstation utilizing one of the following twocolumns and methods: (A) Using a 50×100 mm column (Waters, Externa, C18,5 microns) at 50 mL/min. The mobile phase used was a mixture of solventA (H₂O/10 mM ammonium carbonate at pH about 10, adjusted with conc.NH₄OH) and solvent B (85:15 ACN/water, 10 mM ammonium carbonate at pH ofabout 10 adjusted with conc. NH₄OH). Each purification run utilized a 10minute gradient from 40% to 100% solvent B followed by a 5 minute flowof 100% solvent B. The gradient was followed by a 2 min return to 40%solvent B. (B) Using a 20×50 mm column at 20 mL/min. The mobile phaseused was a mixture of solvent A (H₂O/0.1% TFA) and solvent B (ACN/0.1%TFA) with a 10 min gradient from 5% to 100% solvent B. The gradient isfollowed by a 2 min return to 5% ACN.

Proton NMR Spectra:

Unless otherwise indicated, all ¹H NMR spectra were run on a Varianseries Mercury 300 MHz instrument or a Bruker series 400 MHz instrument.Where so characterized, all observed protons are reported asparts-per-million (ppm) downfield from tetramethylsilane (TMS) or otherinternal reference in the appropriate solvent indicated.

Mass Spectra (MS)

Unless otherwise indicated, all mass spectral data for startingmaterials, intermediates and/or exemplary compounds are reported asmass/charge (m/z), having an (M+H⁺) molecular ion. The molecular ionreported was obtained by electrospray detection method. Compounds havingan isotopic atom, such as bromine and the like, are reported accordingto the detected isotopic pattern, as appreciated by those skilled in theart.

Example 1 Via Method A

Synthesis ofN-Cyclopropyl-3-(8-(2,4-difluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazin-3-yl)-4-methylbenzamide(9) Step 1: 2-(4-Methoxybenzyl)-4,5-dibromopyridazin-3(2H)-one (1)

A mixture of 4,5-dibromopyridazinone (25 g, 98 mmol), anhydrouspotassium carbonate (34 g, 246 mmol), 4-methoxybenzylchloride (14 mL,103 mmol) and tetrabutylammonium bromide (1.6 g, 4.9 mmol) in CH₃CN (200mL) was stirred at 45° C. for 3 h and then at 80° C. for 2 h. Themixture was allowed to cool to 22° C. and filtered through a pad ofCelite. The pad was washed with CH₂Cl₂, followed by EtOAc, and thecombined filtrate was evaporated to dryness. The crude product wassuspended in MeOH and sonicated. The solid was collected by suctionfiltration, washed with MeOH, and air-dried to give2-(4-methoxybenzyl)-4,5-dibromopyridazin-3(2H)-one as a brown solid. Thefiltrate was concentrated and purified by silica gel chromatography,eluting with 20% hexane in CH₂Cl₂, to give2-(4-methoxybenzyl)-4,5-dibromopyridazin-3(2H)-one as a pale yellowsolid. ¹H NMR (400 MHz, CDCl₃) δ ppm 3.78 (s, 3H), 5.25 (s, 2H), 6.85(d, J=8.53 Hz, 2H), 7.40 (d, J=9.03 Hz, 2H), 7.78 (s, 1H).

Step 2: 2-(4-Methoxybenzyl)-5-bromo-4-(methylamino)pyridazin-3(2H)-one(2)

In a glass pressure reactor vessel equipped with a magnetic stir bar,toluene (100 mL) was saturated with anhydrous methylamine at 0° C. then2-(4-methoxybenzyl)-4,5-dibromopyridazin-3(2H)-one (1) (22 g, 59 mmol)was added. The vessel was sealed and the suspension was stirred andheated at 90° C. for 18 h. The resulting suspension was allowed to coolto RT. Anhydrous methylamine was bubbled through the mixture for 15 min,the reactor was sealed again, and the mixture was stirred and heated at90° C. for an additional 18 h. After cooling to RT, the mixture wasconcentrated in vacuo to dryness. The resulting brown solid wassuspended in MeOH and sonicated. The solid was collected by suctionfiltration, washed with MeOH, and dried in vacuo to give2-(4-methoxybenzyl)-5-bromo-4-(methylamino)pyridazin-3(2H)-one as ayellow solid.

MS (ESI, pos. ion) m/z: 324, 326 (M+1, M+3).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.18 (d, J=5.5 Hz, 3H), 3.72 (s, 3H),5.09 (s, 2H), 6.83-6.97 (m, 3H), 7.23 (d, J=8.5 Hz, 2H), 7.69 (s, 1H).

Step 3:1-(4-Methoxybenzyl)-N-methoxy-N-methyl-5-(methylamino)-6-oxo-1,6-dihydropyridazine-4-carboxamide(3)

A glass pressure vessel equipped with a CO regulator was charged with2-(4-methoxybenzyl)-5-bromo-4-(methylamino)pyridazin-3(2H)-one (2) (7.0g, 22 mmol), N,O-dimethylhydroxylamine hydrochloride (3.2 g, 32 mmol),potassium phosphate (14 g, 65 mmol), and toluene (60 mL). The mixturewas purged with Ar then palladium (II) acetate (0.24 g, 1.1 mmol) and4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (1.2 g, 2.2mmol) were added. The vessel was sealed and charged with CO (30 psi) andthe reaction mixture was stirred in a 110° C. oil bath behind a blastshield for 44 h. After cooling to room temperature, the reaction mixturewas diluted with water and CH₂Cl₂. The bi-phasic mixture was filteredthrough a pad of Celite and the pad was washed with CH₂Cl₂. The organiclayer was separated, dried over Na₂SO₄, filtered, and concentrated invacuo to afford the crude product as a brown residue. The crude productwas purified by silica gel chromatography, eluting with a gradient of0-3% MeOH in CH₂Cl₂, to give1-(4-methoxybenzyl)-N-methoxy-N-methyl-5-(methylamino)-6-oxo-1,6-dihydropyridazine-4-carboxamideas a yellow foam. MS (ESI, pos. ion) m/z: 333 (M+1). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.70 (d, J=5.5 Hz, 3H), 3.23 (s, 3H), 3.57 (s, 3H), 3.72(s, 3H), 5.12 (s, 2H), 6.81-6.94 (m, 2H), 7.19-7.31 (m, 3H), 7.52 (s,1H).

Step 4:1-(4-Methoxybenzyl)-5-(methylamino)-6-oxo-1,6-dihydropyridazine-4-carbaldehyde(4)

A solution of1-(4-methoxybenzyl)-N-methoxy-N-methyl-5-(methylamino)-6-oxo-1,6-dihydropyridazine-4-carboxamide(3) (4.60 g, 13.8 mmol) in THF (50.0 mL) was treated with 1.0 M LAH inTHF (15 mL, 15 mmol) at −78° C. The mixture was stirred at 0° C. for 1 hthen quenched carefully at 0° C. with MeOH (1.0 mL), followed by water(1.0 mL) and 1 M aq HCl (1.0 mL). The resulting suspension was filteredand the filtrate was concentrated in vacuo to give1-(4-methoxybenzyl)-5-(methylamino)-6-oxo-1,6-dihydropyridazine-4-carbaldehydeas a pale yellow solid. MS (ESI, pos. ion) m/z: 274 (M+1).

Step 5: Ethyl7-(4-methoxybenzyl)-1-methyl-2,8-dioxo-1,2,7,8-tetrahydropyrido[2,3-d]pyridazine-3-carboxylate(5)

A mixture of1-(4-methoxybenzyl)-5-(methylamino)-6-oxo-1,6-dihydropyridazine-4-carbaldehyde(4) (3.78 g, 13.8 mmol), diethyl malonate (4.20 mL, 27.7 mmol),piperidine (1.44 mL, 14.5 mmol), and EtOH (100 mL) was stirred at refluxin an oil bath for 5 h. The reaction mixture was allowed to stand at RTfor 18 h to afford a suspension. The solid was collected by suctionfiltration, washed with EtOH (10 mL), and dried in vacuo to afford ethyl7-(4-methoxybenzyl)-1-methyl-2,8-dioxo-1,2,7,8-tetrahydropyrido[2,3-d]pyridazine-3-carboxylateas a tan solid. MS (ESI, pos. ion) m/z: 370 (M+1).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.29 (t, J=7.0 Hz, 3H), 3.72 (s, 3H),4.01 (s, 3H), 4.29 (q, J=7.1 Hz, 2H), 5.21 (s, 2H), 6.89 (d, J=8.6 Hz,2H), 7.31 (d, J=8.6 Hz, 2H), 8.27 (s, 1H), 8.38 (s, 1H).

Step 6: Ethyl8-chloro-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazine-3-carboxylate(6)

A solution of ethyl7-(4-methoxybenzyl)-1-methyl-2,8-dioxo-1,2,7,8-tetrahydropyrido[2,3-d]pyridazine-3-carboxylate(5) (2.45 g, 6.63 mmol) in TFA (15 mL) was heated in a microwave at 125°C. for 150 min, then cooled to RT. The volatiles were removed in vacuoto give crude ethyl1-methyl-2,8-dioxo-1,2,7,8-tetrahydropyrido[2,3-d]pyridazine-3-carboxylatewhich was used directly in the next step.

In a RBF equipped with reflux condenser, ethyl1-methyl-2,8-dioxo-1,2,7,8-tetrahydropyrido[2,3-d]pyridazine-3-carboxylate(1.65 g, 6.63 mmol) was treated with phosphorus oxychloride (8.00 mL,85.8 mmol). The reaction mixture was stirred in an oil bath at 110° C.for 90 min, and then cooled to RT. The volatiles were removed in vacuoand the residue was treated with CH₂Cl₂ then concentrated in vacuo. Theresidue was treated with CH₂Cl₂/Et₂O and the resulting suspended solidwas collected by suction filtration and dried in vacuo to give ethyl8-chloro-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazine-3-carboxylateas a green solid. MS (ESI, pos. ion) m/z: 268 (M+1). ¹H NMR (400 MHz,CDCl₃) δ ppm 1.43 (t, J=7.0 Hz, 3H), 4.09 (s, 3H), 4.45 (q, J=7.0 Hz,2H), 8.29 (s, 1H), 9.11 (s, 1H).

Step 7:8-(2,4-Difluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazine-3-carboxylicacid (7)

To a suspension of ethyl8-chloro-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazine-3-carboxylate(6) (1.40 g, 5.23 mmol) in 3:1 1,4-dioxane: 2 M aq Na₂CO₃ (16 mL) wasadded 2,4-difluorophenylboronic acid (1.03 g, 6.54 mmol) andtetrakis(triphenylphosphine)palladium (0) (0.484 g, 0.418 mmol). Thereaction mixture was heated in a microwave at 100° C. for 75 min, thenmore Na₂CO₃ solid (100 mg) was added and the reaction mixture was heatedin the microwave at 100° C. for an additional 2 h. The mixture wasdiluted with water and washed with CH₂Cl₂. The aqueous layer was thenacidified with 5 N HCl to pH ˜2 and extracted with CHCl₃/iPrOH (4:1).The combined organic extracts were dried over MgSO₄, filtered, andconcentrated in vacuo to give8-(2,4-difluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazine-3-carboxylicacid as a brown solid. MS (ESI, pos. ion) m/z: 318 (M+1).

¹H NMR (400 MHz, DMSO-d₆) δ ppm, 3.13 (s, 3H), 7.29-7.40 (m, 1H), 7.50(td, J=2.4, 9.8 Hz, 1H), 7.82 (td, J=6.7, 8.6 Hz, 1H), 8.77 (s, 1H),9.57 (s, 1H).

Step 8:3-Bromo-8-(2,4-difluorophenyl)-1-methylpyrido[3,2-d]pyridazin-2(1H)-one(8)

To a suspension of8-(2,4-difluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazine-3-carboxylicacid (7) (1.00 g, 3.15 mmol) in 10:1 THF:H₂O (11 mL), stirred at 55° C.,was added lithium acetate dihydrate (67 mg, 0.66 mmol). The mixture wasstirred at 55° C. and treated with NBS (1.51 g, 8.48 mmol) in threeequal portions at 30 min intervals. After addition of NBS was complete,the reaction mixture was stirred an additional 1 h at 55° C. In aseparate flask, a suspension of8-(2,4-difluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazine-3-carboxylicacid (7) (0.92 g, 2.89 mmol) in 10:1 THF:H₂O (10 mL) stirred at 55° C.was treated with lithium acetate dihydrate (62 mg, 0.61 mmol) followedby NBS (1.39 g, 7.80 mmol) under the same conditions. Upon completereaction, the two reaction mixtures were combined, diluted with water,and extracted with CH₂Cl₂. The combined organic layers were washed with20% THF in water, dried over MgSO₄, filtered, and concentrated in vacuo.The resulting residue was purified by silica gel chromatography [elutingwith a gradient of 10-40% B in A where the eluents were: A=CH₂Cl₂;B=1:49.5:49.5 MeOH:EtOAc:CH₂Cl₂] to give3-bromo-8-(2,4-difluorophenyl)-1-methylpyrido[3,2-d]pyridazin-2(1H)-oneas a yellow solid. MS (ESI, pos. ion) m/z: 350, 352 (M+1, M+3).

¹H NMR (400 MHz CDCl₃) δ ppm 3.36 (s, 3H), 6.92-7.04 (m, 1H), 7.15 (td,J=2.0, 8.2 Hz, 1H), 7.78 (td, J=6.3, 8.4 Hz, 1H), 8.26 (s, 1H), 9.17 (s,1H).

Step 9:N-Cyclopropyl-3-(8-(2,4-difluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazin-3-yl)-4-methylbenzamide(9)

To a suspension of3-bromo-8-(2,4-difluorophenyl)-1-methylpyrido[3,2-d]pyridazin-2(1H)-one(8) (80.0 mg, 0.227 mmol) in 3:1 1,4-dioxane: 1 M aq Na₂CO₃ (3.2 mL) wasaddedN-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(82.1 mg, 0.273 mmol) and tetrakis(triphenylphosphine)palladium (0)(21.0 mg, 0.0182 mmol). The reaction mixture was stirred and heated in amicrowave at 100° C. for 55 min and then cooled to room temperature. Themixture was diluted with water and extracted with CHCl₃/iPrOH (4:1). Thecombined organic extract was washed with 2 M Na₂CO₃, dried over MgSO₄,filtered, and concentrated in vacuo. The residue was purified by silicagel chromatography [eluting with a gradient of 40-50% B in A where theeluents were: A=CH₂Cl₂; B=4% MeOH in EtOAc] to giveN-cyclopropyl-3-(8-(2,4-difluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazin-3-yl)-4-methylbenzamideas a white solid. MS (ESI, pos. ion) m/z: 447 (M+1). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.52-0.60 (m, 2H), 0.64-0.73 (m, 2H), 2.21 (s, 3H), 2.85(td, J=3.9, 7.3 Hz, 1H), 3.16 (s, 3H), 7.32-7.42 (m, 2H), 7.45-7.54 (m,1H), 7.74 (d, J=1.4 Hz, 1H), 7.79-7.91 (m, 2H), 8.19 (s, 1H), 8.41 (d,J=3.9 Hz, 1H), 9.45 (s, 1H).

Example 2 Via Method B

Synthesis of3-(8-(2-chlorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazin-3-yl)-N-(isoxazol-3-yl)-4-methylbenzamide

To a suspension of3-(8-(2-chlorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazin-3-yl)-4-methylbenzoicacid (100 mg, 0.25 mmol; prepared by the general method shown in scheme2) in DCM at 0° C. was added oxalyl chloride (43.7 μl, 0.49 mmol)followed by a drop of DMF. The reaction was stirred at 0° C. for 15 minthen warmed to RT for 1 h. The volatile solvents were removed underreduced pressure and the residue was dissolved in DCM. To the reactionmixture was added 3-aminoisoxazole (54.6 μl, 0.74 mmol) andN,N-diisopropylethylamine (42.9 μl, 0.25 mmol). After the reactionmixture was stirred at RT for 3 h, the solvent was then removed invacuo. The residual crude material was purified with Reverse phase-HPLC[elution gradient of 10-50% of (0.1% TFA in acetonitrile) in (0.1% ofTFA) in water] and the fractions containing the product were combinedand concentrated in vacuo. The remaining crude mixture was stirred withEtOAc and sat. Na₂CO₃. The organic layer was separated and washed withbrine, separated, then dried with sodium sulfate and concentrated togive3-(8-(2-chlorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazin-3-yl)-N-(isoxazol-3-yl)-4-methylbenzamide(33.0 mg) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.43 (1H,s), 9.48 (1H, s), 8.81 (1H, s), 8.24 (1H, s), 7.95-8.10 (2H, m),7.76-7.86 (1H, m), 7.56-7.74 (3H, m), 7.46 (1H, d, J=8.0 Hz), 7.05 (1H,s), 3.12 (3H, s), 2.24 (3H, s); Mass Found: LC-MS (ESI): m/e=472/474

These detailed descriptions of the Examples fall within the scope, andserve to exemplify the above-described General Synthetic Procedureswhich form part of the invention. These detailed descriptions are notintended as a restriction on the scope of the invention.

The following Examples in Table 1 will further assist in understandingand appreciating the invention. The compounds of examples 1-33 were madein accordance with exemplary methods A and B, which corresponds to abovedescribed Examples 1 and 2 above, respectively, and more generally toschemes 1 and 2. The compound examples were named according to the ACDnaming convention, as associated with ISIS software. The mass spectraldata is recorded M+H⁺, which is the positive ion as measured by anelectrospray ionization method. The biological assay data is providedfor those exemplary compounds in Table 1 which were tested in, and datacalculated from, the human whole blood and cellular assays. Not everycompound example was run in the assays at the time of filing of thisapplication, and accordingly no data is provided in the Table.

TABLE 1 WB TNF/IL8 p38a Ex. MS IC50 IC50 No Name (M + H+) Method (nM)(nM) 1 N-cyclopropyl-3-(8-(2,4-difluorophenyl)-1- 447 A 2.1 2.3methyl-2-oxo-1,2-dihydropyrido[3,2- d]pyridazin-3-yl)-4-methylbenzamide2 3-(8-(2,4-difluorophenyl)-1-methyl-2-oxo- 407 A 13 31,2-dihydropyrido[3,2-d]pyridazin-3-yl)-4- methylbenzamide 3N-cyclopropyl-3-(8-(2,4-difluorophenyl)-1- 465 A 1.6 1.7methyl-2-oxo-1,2-dihydropyrido[3,2- d]pyridazin-3-yl)-5-fluoro-4-methylbenzamide 4 4-chloro-3-(8-(2,4-difluorophenyl)-1- 428A >2500 >1000 methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazin-3-yl)benzoic acid 5 4-chloro-N-cyclopropyl-3-(8-(2,4-467/469 A 8.3 1.6 difluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazin-3- yl)benzamide 6N-cyclopropyl-4-methyl-3-(1-methyl-2- 425 A 1 11.4oxo-8-o-tolyl-1,2-dihydropyrido[3,2- d]pyridazin-3-yl)benzamide 7N-cyclopropyl-3-fluoro-4-methyl-5-(1- 443 A 1.2 1.5methyl-2-oxo-8-o-tolyl-1,2- dihydropyrido[3,2-d]pyridazin-3-yl)benzamide 8 3-(8-(2-chlorophenyl)-1-methyl-2-oxo-1,2- 445/447 A 1.71.6 dihydropyrido[3,2-d]pyridazin-3-yl)-N- cyclopropyl-4-methylbenzamide9 N-cyclopropyl-3-(8-(2-fluoro-4- 497 A 7.3 2(trifluoromethyl)phenyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazin-3-yl)-4- methylbenzamide 10N-cyclopropyl-4-methyl-3-(1-methyl-2- 479 A 4.2 2.9oxo-8-(2-(trifluoromethyl)phenyl)-1,2- dihydropyrido[3,2-d]pyridazin-3-yl)benzamide 11 N-cyclopropyl-3-fluoro-4-methyl-5-(1- 497 A 2.2 2.4methyl-2-oxo-8-(2- (trifluoromethyl)phenyl)-1,2-dihydropyrido[3,2-d]pyridazin-3- yl)benzamide 12N-cyclopropyl-3-(8-(4-fluoro-2- 443 A 2.0 2.5methylphenyl)-1-methyl-2-oxo-1,2- dihydropyrido[3,2-d]pyridazin-3-yl)-4-methylbenzamide 13 N-cyclopropyl-3-(8-(2-chloro-4- 463/465 A 4.3 2.8fluorophenyl)-1-methyl-2-oxo-1,2- dihydropyrido[3,2-d]pyridazin-3-yl)-4-methylbenzamide 14 3-(8-(2-chlorophenyl)-1-methyl-2-oxo-1,2- 463 A 1.12.4 dihydropyrido[2,3-d]pyridazin-3-yl)-N-cyclopropyl-5-fluoro-4-methylbenzamide 153-(8-(2,4-difluorophenyl)-1-methyl-2-oxo- 487 B 4.1 7.51,2-dihydropyrido[2,3-d]pyridazin-3-yl)-4-methyl-N-(1-methyl-1H-pyrazol-5- yl)benzamide 16N-cyclopropyl-3-fluoro-5-(8-(4-fluoro-2- 461 A 2.3 3methylphenyl)-1-methyl-2-oxo-1,2- dihydropyrido[2,3-d]pyridazin-3-yl)-4-methylbenzamide 17 3-(8-(2-chloro-4-fluorophenyl)-1-methyl-2- 481/483 A1.9 1.8 oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-N-cyclopropyl-5-fluoro-4- methylbenzamide 183-(8-(2-chloro-5-fluorophenyl)-1-methyl-2- 463 A 2.2 1.7oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-N-cyclopropyl-4-methylbenzamide 193-(8-(2-chloro-5-fluorophenyl)-1-methyl-2- 481 A 1.5 1.6oxo-1,2-dihydropyrido[2,3-d]pyridazin-3- yl)-N-cyclopropyl-5-fluoro-4-methylbenzamide 20 3-(8-(2-chloro-4-fluorophenyl)-1-methyl-2- 477/479 A15.6 4.1 oxo-1,2-dihydropyrido[2,3-d]pyridazin-3- yl)-4-methyl-N-(1-methylcyclopropyl)benzamide 213-(8-(2-chloro-4-fluorophenyl)-1-methyl-2- 490/492 B 1.5 0.8oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-N-3-isoxazolyl-4-methylbenzamide 22N-cyclopropyl-3-(8-(2,4-difluorophenyl)-1- 479 A 1.0 1.3ethyl-2-oxo-1,2-dihydropyrido[2,3- d]pyridazin-3-yl)-5-fluoro-4-methylbenzamide 23 N-cyclopropyl-3-(8-(2,4-difluorophenyl)-1- 461 A 1.51.5 ethyl-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-4-methylbenzamide 243-(8-(2-chloro-4-fluorophenyl)-1-methyl-2- 506/508 B 9.3 1oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-4-methyl-N-1,3-thiazol-2-ylbenzamide 253-(8-(2-chlorophenyl)-1-methyl-2-oxo-1,2- 472/474 B 1 0.9dihydropyrido[2,3-d]pyridazin-3-yl)-N-3- isoxazolyl-4-methylbenzamide 26N-cyclopropyl-4-methyl-3-(1-methyl-8-(2- 503.1 A 10 3.3methyl-4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3- yl)benzamide 27N-cyclopropyl-3-fluoro-4-methyl-5-(1- 521.1 A 3.9 2.5methyl-8-(2-methyl-4- (methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3- yl)benzamide 283-(8-(2-chlorophenyl)-1-ethyl-2-oxo-1,2- 459 A 1 1dihydropyrido[2,3-d]pyridazin-3-yl)-N- cyclopropyl-4-methylbenzamide 293-(8-(2,4-difluorophenyl)-1-methyl-2-oxo- 461 A 5 31,2-dihydropyrido[2,3-d]pyridazin-3-yl)-4- methyl-N-(1-methylcyclopropyl)benzamide 30N-cyclopropyl-4-(8-(2,4-difluorophenyl)-1- 448 A 38 14methyl-2-oxo-1,2-dihydropyrido[2,3- d]pyridazin-3-yl)-5-methyl-2-pyridinecarboxamide 31 3-(8-(2,4-difluorophenyl)-1-methyl-2-oxo- 421 B30 2.7 1,2-dihydropyrido[2,3-d]pyridazin-3-yl)- N,4-dimethylbenzamide 323-(8-(2,4-difluorophenyl)-1-methyl-2-oxo- 490.1 B 7.3 1.21,2-dihydropyrido[2,3-d]pyridazin-3-yl)-4-methyl-N-1,3-thiazol-2-ylbenzamide 333-(8-(2,4-difluorophenyl)-1-methyl-2-oxo- 473 B 1.7 11,2-dihydropyrido[2,3-d]pyridazin-3-yl)-N-3-isoxazolyl-4-methylbenzamide

The following Examples in Table 2 are additional representativecompounds which will further assist in understanding and appreciatingthe invention. The compounds are named according to the ACD namingconvention, as associated with ISIS software.

TABLE 2 Ex. No. Compound Name Chemical Structure 343-(8-(2,4-difluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-4-methyl-N- phenylbenzamide

35 3-(8-(2,4-difluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-4-methyl-N- (pyridin-4-yl)benzamide

36 8-(2,4-difluorophenyl)-1-methyl-3-(2-methyl-5-(morpholine-4-carbonyl)phenyl)pyrido[2,3-d]pyridazin- 2(1H)-one

37 N-(cyclopropylmethyl)-3-(8-(2,4-difluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)- 4-methylbenzamide

38 N-(3-(8-(2,4-difluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-4- methylphenyl)acetamide

39 N-(3-(8-(2,4-difluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-4- methylphenyl)methanesulfonamide

40 1-(3-(8-(2,4-difluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-4-methylphenyl)- 3-methylurea

41 3-(8-(2-chloro-4-(methylsulfonyl)phenyl)-1-methyl-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-N-cyclopropyl-4-methylbenzamide

42 N-cyclopropyl-4-methyl-3-(1-methyl-8-(4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)benzamide

43 N-cyclopropyl-4-methyl-3-(1-methyl-8-(3-methyl-1H-pyrazol-4-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin- 3-yl)benzamide

44 N-cyclopropyl-4-methyl-3-(1-methyl-8-morpholino-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)benzamide

45 N-cyclopropyl-3-(8-isopropyl-1-methyl-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-4- methylbenzamide

46 N-cyclopropyl-3-(8-(isopropylamino)-1-methyl-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-4- methylbenzamide

47 N-cyclopropyl-3-(8-isopropoxy-1-methyl-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-4- methylbenzamide

48 N-cyclopropyl-4-methyl-3-(1-methyl-2-oxo-8-(phenylthio)-1,2-dihydropyrido[2,3-d]pyridazin-3- yl)benzamide

49 N-cyclopropyl-3-(8-(2,4-difluorophenyl)-1-methyl-2-thioxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-4- methylbenzamide

50 N-cyclopropyl-3-(8-(2,4-difluorophenyl)-1-methoxy-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-4- methylbenzamide

The following compounds in Table 3 are additional representativeexamples of Formula I as provided by the present invention.

TABLE 3

Ex. No. R¹ R⁴ R⁵ R⁶ R⁷ or R⁸ 51 3,5-difluoro-Ph —CH₂CH₃ H —C(O)NH—oxazolyl 52 morpholine —CH₃ H —C(O)NH— methyl or cyclopropyl 53piperazine —CH₂CH₃ H —C(O)NH— methyl or cyclopropyl 54 piperidine —CH₃ H—C(O)NH— methyl or cyclopropyl 55 phenyl —CH₃ F —C(O)NH— methyl orcyclopropyl 56 m-CH₃-phenyl- —CH₂CH₃ Cl —C(O)NH— methyl or cyclopropyl57 m-Cl-phenyl- —CH₂CH₃ OCH₃ —C(O)NH— methyl or cyclopropyl 58o-CH₃-phenyl —CH₂CH₃ H —NHC(O)— pyridyl 59 —S-Phenyl —CH₃ F —C(O)NH—morpholinyl 60 —NH-phenyl —OCH₃ Cl —C(O)NH— methyl 61 —O-isopropyl—CH₂CH₃ H —NHC(O)— ethyl 62 morpholine —CH₃ F —C(O)NH— propyl 63N—CH₃-imidazole —OCH₃ Cl —S(O)₂NH— imidazolyl 64 pyrazole —CH₂CH₃ H—C(O)NH— pyrazolyl 65 triazole —CH₃ F —NHC(O)— furanyl 66 thiophene—OCH₃ Cl —C(O)NH— thiadiazolyl 67 2-CH₃-thiophene —CH₂CH₃ H —C(O)NHC(O)—isothiazolyl 68 —NH-cyclohexyl —CH₂CH₃ F —S(O)₂NH— cyclopropyl 69—NH-cyclopropyl —CH₃ Cl —C(O)NH— methyl 70 —O-isobutyl —OCH₃ H —NHS(O)₂—Cyclopropyl 71 2,4-difluoro-Ph —CH₂CH₃ H —C(O)NH— isothiazolyl 722,6-difluoro-Ph —CH₃ F —NHC(O)— cyclopropyl 73 2,6-difluoro-Ph —CH₃ Cl—C(O)NH— methyl 74 o-CH₃-phenyl —OCH₃ OCH₃ —C(O)NH— cyclopropyl 75—S-Phenyl —CH₂CH₃ H —C(O)NH— imidazolyl 76 —NH-phenyl —CH₃ F —NHC(O)—pyrazolyl 77 —O-isopropyl —OCH₃ Cl —C(O)NH— furanyl 78 morpholine—CH₂CH₃ OCH₃ —S(O)₂NH— thiadiazolyl 79 3,5-difluoro-Ph —CH₂CH₃ H—C(O)NH— isoxazolyl 80 morpholine —CH₃ H —C(O)NH— pyrazolyl 81piperazine —CH₂CH₃ H —C(O)NH— imidazolyl 82 piperidine —CH₃ H —C(O)NH—triazolyl 83 phenyl —CH₃ F —C(O)NH— tetrazolyl 84 m-CH₃-phenyl- —CH₂CH₃Cl —C(O)NH— thioazolyl 85 2-Cl-phenyl —CH₂CH₃ OCH₃ —C(O)NH— isothiazolyl86 2-CH₃-phenyl —CH₂CH₃ H —NHC(O)— phenyl 87 4-CH₃-phenyl —CH₃ H—NHC(O)— cyclopropyl 88 4-Cl-phenyl —CH₂CH₃ di-F —NHC(O)NH— ethyl 893-Cl-phenyl —CH₃ di-Cl —NHC(O)— propyl 90 3-CH₃-phenyl —CH₃ OCH₃—NHC(O)— butyl 91 2-thiophene —CH₂CH₃ CF₃ —NHC(O)NH— isopropyl 923-thiophene —CH₃ OCF₃ —NHC(O)— isobutyl 93 2-pyridine —CH₂CH₃ OH—NHC(O)— cyclopentyl 94 1-morpholinyl —(CH₂)₂CH₃ F —C(O)NH— ethyl 951-piperazinyl —CH₃ Cl —C(O)NH— oxazolyl 96 1-piperidinyl —CH₂CH₃ OCH₃—C(O)NH— isoxazolyl 97 3,5-difluoro-Ph —CH₃ F —C(O)NH— isothiazolyl 983-Cl-phenyl —CH₂CH₃ Cl —C(O)NH— thiazolyl 99 3-CH₃-phenyl —CH₃ OCH₃—C(O)NH— ethyl 100 2-thiophene —CH₂CH₃ H —C(O)NH— ethyl 101 phenyl —CH₃—NHCH₃ —NHC(O)— isoxazolyl 102 3-amido-1-pyrrolidinyl —CH₃ H —NHC(O)—pyrazolyl 103 3-amido-1-piperidinyl —CH₂CH₃ H —NHC(O)— imidazolyl 1044-amido-1-piperidinyl —CH₃ F —NHC(O)— triazolyl 105 4N—CH₃-1-piperizinyl—CH₂CH₃ Cl —S(O)₂NH— tetrazolyl 106 2-Cl-phenyl —(CH₂)₂CH₃ OCH₃—S(O)₂NH— thioazolyl 107 2-CH₃-phenyl —CH₃ F —S(O)₂NH— isothiazolyl 1084-CH₃-phenyl —CH₂CH₃ Cl —S(O)₂NH— phenyl 109 4-Cl-phenyl —CH₂CH₃ OCH₃—S(O)₂NH— cyclopropyl 110 3-Cl-phenyl —CH₃ F —C(O)NH— ethyl 1113-CH₃-phenyl —CH₃ —NHCH₃ —C(O)NH— propyl 112 2-thiophene —CH₂CH₃ H—C(O)NH— ethyl 113 3-thiophene —(CH₂)₂CH₃ H —C(O)NH— quinolinyl 1142-pyridine —CH₃ F —C(O)NH— isoquinolinyl 115 1-morpholinyl —CH₂CH₃ Cl—C(O)NH— cyclopropyl 116 1-piperazinyl —CH₂CH₃ CN —NHC(O)— propyl 1171-piperidinyl —CH₃ CF₃ —NHC(O)— cyclopropyl 118 cyclohexyl-N— —CH₃ OH—NHC(O)— cyclopropyl 119 morpholine-(CH₂)₂—N— —CH₂CH₃ NHCH₃ —NHC(O)—propyl 120 (CH₃)₂N—(CH₂)₂— —(CH₂)₂CH₃ H —NHC(O)— propyl 121(C₂H₅)₂N—(CH₂)₂— —CH₃ acetyl —NHC(O)— cyclopropyl 1223-OH-1-pyrrolidinyl —CH₂CH₃ H —NHC(O)— propyl 123 —CH₂CH₃ —CH₂CH₃ H—NHC(O)— propyl 124 —(CH₂)₂CH₃ —CH₂CH₃ acetyl —C(O)NH— isoxazolyl 125—CH₃ —(CH₂)₂CH₃ H —C(O)NH— pyrazolyl 126 4N—CH₃-1-piperizinyl —CH₃ H—C(O)NH— imidazolyl 127 2-Cl-phenyl —CH₂CH₃ H —C(O)NH— triazolyl 1282-CH₃-phenyl —CH₂CH₃ H —C(O)NH— tetrazolyl 129 4-CH₃-phenyl —CH₃ CN—C(O)NH— thioazolyl 130 4-Cl-phenyl —CH₃ H —S(O)₂NH— isothiazolyl 1313-Cl-phenyl —CH₂CH₃ H —S(O)₂NH— phenyl 132 3-CH₃-phenyl —(CH₂)₂CH₃ H—S(O)₂NH— cyclopropyl 133 2-thiophene —CH₃ H —S(O)₂NH— ethyl 1343-thiophene —CH₂CH₃ H —S(O)₂NH— propyl 135 2-pyridine —CH₂CH₃ H—S(O)₂NH— isoxazolyl 136 4-F-phenyl —CH₃ CH₃ —S(O)₂NH— pyrazolyl

While the examples and schemes described above provide processes forsynthesizing compounds, and intermediates thereof, of Formulas I, I-A,I-B, I-C and II, it should be appreciated that other methods may beutilized to prepare such compounds. Methods involving the use ofprotecting groups may be used. Particularly, if one or more functionalgroups, for example carboxy, hydroxy, amino, or mercapto groups, are orneed to be protected in preparing the compounds of the invention,because they are not intended to take part in a specific reaction orchemical transformation, various known conventional protecting groupsmay be used. For example, protecting groups typically utilized in thesynthesis of natural and synthetic compounds, including peptides,nucleic acids, derivatives thereof and sugars, having multiple reactivecenters, chiral centers and other sites potentially susceptible to thereaction reagents and/or conditions, may be used. Persons of ordinaryskill in the art know, or can easily establish, which protecting groupsare suitable with the reactions described herein.

The protection of functional groups by protecting groups, the protectinggroups themselves, and their removal reactions (commonly referred to as“deprotection”) are described, for example, in standard reference works,such as J. F. W. McOmie, Protective Groups in Organic Chemistry, PlenumPress, London and New York (1973), in T. W. Greene, Protective Groups inOrganic Synthesis, Wiley, New York (1981), in The Peptides, Volume 3, E.Gross and J. Meienhofer editors, Academic Press, London and New York(1981), in Methoden der Organischen Chemie (Methods of OrganicChemistry), Houben Weyl, 4^(th) edition, Volume 15/1, Georg ThiemeVerlag, Stuttgart (1974), in H.-D. Jakubke and H. Jescheit, Aminosauren,Peptide, Proteine (Amino Acids, Peptides, Proteins), Verlag Chemie,Weinheim, Deerfield Beach, and Basel (1982), and in Jochen Lehmann,Chemie der Kohlenhydrate: Monosaccharide and Derivate (Chemistry ofCarbohydrates: Monosaccharides and Derivatives), Georg Thieme Verlag,Stuttgart (1974).

Salts of a compound of the invention having a salt-forming group may beprepared in a conventional manner or manner known to persons skilled inthe art. For example, acid addition salts of compounds of the inventionmay be obtained by treatment with an acid or with a suitable anionexchange reagent. A salt with two acid molecules (for example adihalogenide) may also be converted into a salt with one acid moleculeper compound (for example a monohalogenide); this may be done by heatingto a melt, or for example by heating as a solid under a high vacuum atelevated temperature, for example from 50° C. to 170° C., one moleculeof the acid being expelled per molecule of the compound.

Acid salts can usually be converted to free-base compounds, e.g. bytreating the salt with suitable basic agents, for example with alkalimetal carbonates, alkali metal hydrogen carbonates, or alkali metalhydroxides, typically potassium carbonate or sodium hydroxide. Exemplarysalt forms and their preparation are described herein in the Definitionsection of the application.

All synthetic procedures described herein can be carried out under knownreaction conditions, advantageously under those described herein, eitherin the absence or in the presence (usually) of solvents or diluents. Asappreciated by those of ordinary skill in the art, the solvents shouldbe inert with respect to, and should be able to dissolve, the startingmaterials and other reagents used. Solvents should be able to partiallyor wholly solubilize the reactants in the absence or presence ofcatalysts, condensing agents or neutralizing agents, for example ionexchangers, typically cation exchangers for example in the H⁺ form. Theability of the solvent to allow and/or influence the progress or rate ofthe reaction is generally dependant on the type and properties of thesolvent(s), the reaction conditions including temperature, pressure,atmospheric conditions such as in an inert atmosphere under argon ornitrogen, and concentration, and of the reactants themselves.

Suitable solvents for conducting reactions to synthesize compounds ofthe invention include, without limitation, water; esters, includinglower alkyl-lower alkanoates, e.g., ethyl acetate; ethers includingaliphatic ethers, e.g., Et₂O and ethylene glycol dimethyl ether orcyclic ethers, e.g., THF; liquid aromatic hydrocarbons, includingbenzene, toluene and xylene; alcohols, including MeOH, EtOH, 1-propanol,IPOH, n- and t-butanol; nitriles including CH₃CN; halogenatedhydrocarbons, including CH₂Cl₂, CHCl₃ and CCl₄; acid amides includingDMF; sulfoxides, including DMSO; bases, including heterocyclic nitrogenbases, e.g. pyridine; carboxylic acids, including lower alkanecarboxylicacids, e.g., AcOH; inorganic acids including HCl, HBr, HF, H₂SO₄ and thelike; carboxylic acid anhydrides, including lower alkane acidanhydrides, e.g., acetic anhydride; cyclic, linear, or branchedhydrocarbons, including cyclohexane, hexane, pentane, isopentane and thelike, and mixtures of these solvents, such as purely organic solventcombinations, or water-containing solvent combinations e.g., aqueoussolutions. These solvents and solvent mixtures may also be used in“working-up” the reaction as well as in processing the reaction and/orisolating the reaction product(s), such as in chromatography.

The invention further encompasses “intermediate” compounds, includingstructures produced from the synthetic procedures described, whetherisolated or not, prior to obtaining the finally desired compound.Structures resulting from carrying out steps from a transient startingmaterial, structures resulting from divergence from the describedmethod(s) at any stage, and structures forming starting materials underthe reaction conditions are all “intermediates” included in theinvention. Further, structures produced by using starting materials inthe form of a reactive derivative or salt, or produced by a compoundobtainable by means of the process according to the invention andstructures resulting from processing the compounds of the invention insitu are also within the scope of the invention.

New starting materials and/or intermediates, as well as processes forthe preparation thereof, are likewise provided by this invention.Starting materials of the invention, are either known, commerciallyavailable, or can be synthesized in analogy to or according to methodsthat are known in the art. Many starting materials may be preparedaccording to known processes and, in particular, can be prepared usingprocesses described in the examples. In synthesizing starting materials,functional groups may be protected with suitable protecting groups whennecessary. Protecting groups, their introduction and removal aredescribed above.

In synthesizing a compound of formulas I, I-A, I-B, I-C and II accordingto a desired procedure, the steps may be performed in an order suitableto prepare the compound, including a procedure described herein or by analternate order of steps described herein, and may be preceded, orfollowed, by additional protection/deprotection steps as necessary. Theprocedures may further use appropriate reaction conditions, includinginert solvents, additional reagents, such as bases (e.g., LDA, DIEA,pyridine, K₂CO₃, and the like), catalysts, and salt forms of the above.The intermediates may be isolated or carried on in situ, with or withoutpurification. Purification methods are known in the art and include, forexample, crystallization, chromatography (liquid and gas phase, and thelike), extraction, distillation, trituration, reverse phase HPLC and thelike. Reactions conditions such as temperature, duration, pressure, andatmosphere (inert gas, ambient) are known in the art and may be adjustedas appropriate for the reaction. Synthetic chemistry transformations andprotecting group methodologies (protection and deprotection) useful insynthesizing the inhibitor compounds described herein are known in theart and include, for example, those such as described in R. Larock,Comprehensive Organic Transformations, VCH Publishers (1989); T. W.Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3^(rd)edition, John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser andFieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); A.Katritzky and A. Pozharski, Handbook of Heterocyclic Chemistry, 2ndedition (2001); M. Bodanszky, A. Bodanszky, The Practice of PeptideSynthesis, Springer-Verlag, Berlin Heidelberg (1984); J. Seyden-Penne,Reductions by the Alumino- and Borohydrides in Organic Synthesis, 2^(nd)edition, Wiley-VCH, (1997); and L. Paquette, editor, Encyclopedia ofReagents for Organic Synthesis, John Wiley and Sons (1995).

In one embodiment, the present invention provides a method of making acompound of Formula I, the method comprising the step of reacting acompound 7

wherein R¹, R², R³, R⁴ and X are as defined herein and Y is a halogen,with a boronic acid having a general formula

wherein R⁵ and R⁶ are as defined herein, to make a compound of FormulaI.

In another embodiment, the present invention provides a method of makinga compound of Formula I-B, the method comprising the step of reacting acompound 7-B

wherein R¹, R², R³, R⁴ and X are as defined herein and Y is a halogen,with a boronic acid having a general formula

wherein each R⁵ and R⁷ are as defined herein, to make a compound ofFormula I-B.

In another embodiment, the present invention provides a method of makinga compound of Formula I-C, the method comprising the step of reacting acompound 7-C

wherein R¹, R², R³ and R⁴ are as defined herein and Y is a halogen, witha boronic acid having a general formula

wherein R⁵, R⁵, R⁷ and R⁸ are as defined herein, to make a compound ofFormula I-C.

Compounds of the present invention can possess, in general, one or moreasymmetric carbon atoms and are thus capable of existing in the form ofoptical isomers including, without limitation, racemates and racemicmixtures, scalemic mixtures, single enantiomers, individualdiastereomers and diastereomeric mixtures. All such isomeric forms ofthese compounds are expressly included in the present invention.

The optical isomers can be obtained by resolution of the racemicmixtures according to conventional processes, e.g., by formation ofdiastereoisomeric salts, by treatment with an optically active acid orbase. Examples of appropriate acids are tartaric, diacetyltartaric,dibenzoyltartaric, ditoluoyltartaric, and camphorsulfonic acid and thenseparation of the mixture of diastereoisomers by crystallizationfollowed by liberation of the optically active bases from these salts. Adifferent process for separation of optical isomers involves the use ofa chiral chromatography column optimally chosen to maximize theseparation of the enantiomers. Still another available method involvessynthesis of covalent diastereoisomeric molecules by reacting compoundsof the invention with an optically pure acid in an activated form or anoptically pure isocyanate. The synthesized diastereoisomers can beseparated by conventional means such as chromatography, distillation,crystallization or sublimation, and then hydrolyzed to deliver theenantiomerically pure compound. The optically active compounds of theinvention can likewise be obtained by using optically active startingmaterials. These isomers may be in the form of a free acid, a free base,an ester or a salt.

The compounds of this invention may also be represented in multipletautomeric forms. The invention expressly includes all tautomeric formsof the compounds described herein.

The compounds may also occur in cis- or trans- or E- or Z-double bondisomeric forms. All such isomeric forms of such compounds are expresslyincluded in the present invention. All crystal forms of the compoundsdescribed herein are expressly included in the present invention.

Substituents on ring moieties (e.g., phenyl, thienyl, etc.) may beattached to specific atoms, whereby they are intended to be fixed tothat atom, or they may be drawn unattached to a specific atom, wherebythey are intended to be attached at any available atom that is notalready substituted by an atom other than H (hydrogen).

The present invention also includes isotopically-labelled compounds,which are identical to those recited herein, but for the fact that oneor more atoms are replaced by an atom having an atomic mass or massnumber different from the atomic mass or mass number usually found innature. Examples of isotopes that can be incorporated into compounds ofthe invention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁶O,¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl.

Compounds of the present invention that contain the aforementionedisotopes and/or other isotopes of other atoms are within the scope ofthis invention. Certain isotopically-labelled compounds of the presentinvention, for example those into which radioactive isotopes such as ³Hand ¹⁴C are incorporated, are useful in drug and/or substrate tissuedistribution assays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C,isotopes are particularly preferred for their ease of preparation anddetection. Further, substitution with heavier isotopes such asdeuterium, i.e., ²H, can afford certain therapeutic advantages resultingfrom greater metabolic stability, for example increased in vivohalf-life or reduced dosage requirements and, hence, may be preferred insome circumstances. Isotopically labelled compounds of this inventioncan generally be prepared by substituting a readily availableisotopically labelled reagent for a non-isotopically labelled reagent.

Biological Evaluation

The compounds of the invention may be modified by appending appropriatefunctionalities to enhance selective biological properties. Suchmodifications are known in the art and include those which increasebiological penetration into a given biological compartment (e.g., blood,lymphatic system, central nervous system), increase oralbioavailability, increase solubility to allow administration byinjection, alter metabolism and alter rate of excretion. By way ofexample, a compound of the invention may be modified to incorporate ahydrophobic group or “greasy” moiety in an attempt to enhance thepassage of the compound through a hydrophobic membrane, such as a cellwall.

Although the pharmacological properties of the compounds of theinvention (Formulas I, I-A, I-B and I-C, and Formula II) vary withstructural change, in general, activity possessed by compounds ofFormulas I and II may be demonstrated both in vitro as well as in vivo.Particularly, the pharmacological properties of the compounds of thisinvention may be confirmed by a number of pharmacological in vitroassays, as well as in-vivo animal models.

The following assays were used to characterize the ability of compoundsof the invention to modulate the activity of human p38 enzyme, inhibitthe production of TNF-α and interleukin cytokines, including IL-1,IL-1β, IL-6 and IL-8 and/or evaluate efficacy of a compound in an invivo animal model. Another assay, a cyclooxygenase enzyme (COX-1 andCOX-2) inhibition activity in vitro assay, can be used to characterizethe ability of compounds of the invention to inhibit COX-1 and/or COX-2.

Purified and Activated Recombinant Human p38α AssayKinase Reaction Buffer: Kinase reaction buffer for p38α HTRF assaysconsists of 50 mM Tris-pH 7.5, 5 mM MgCl₂, 0.1 mg/mL BSA, 100 μM Na₃VO₄and 0.5 mM DTT.HTRF Detection Buffer: HTRF detection buffer contains 100 mM HEPES-pH7.5, 100 mM NaCl, 0.1% BSA, 0.05% Tween-20, and 10 mM EDTA.Serial Dilution of Compounds: Compounds were dissolved in 100% DMSO andserially diluted (3 fold, 10 point) in a polypropylene 96-wellmicrotiter plate (drug plate). The final starting concentration ofcompounds in the p38α enzymatic assays was 1 μM. Columns 6 and 12 (HIcontrols and LO controls respectively) in the drug plate were reservedas controls and contained only DMSO.Kinase Reaction: The p38α kinase reactions were carried out in apolypropylene 96-well black round bottom assay plate in total volume of30 μL kinase reaction buffer.Appropriate concentration of purified and activated enzyme (recombinanthuman) was mixed with indicated concentration of ATP and 100 nMGST-ATF2-Avitag, in the presence or absence (HI control) of Compound.See table below for actual concentrations. In the absence of substrate,the background was measured as LO control. The reaction was allowed toincubate for 1 hour at RT.Assay Reagent Concentrations: The final reagent concentrations were 1 nMp38α and 50 μM ATP. The Km for ATP of the enzyme was 103 μM, giving aratio of ATP concentration to Km of 0.49.HTRF Detection: The kinase reaction was terminated and phospho-ATF2 wasrevealed by addition of 30 μL of HTRF detection buffer supplemented with0.1 nM Eu-anti-pTP and 4 nM SA-APC. After 60 minutes incubation at roomtemperature, the assay plate was read in a Discovery Plate Reader. Thewells were excited with coherent 320 nm light and the ratio of delayed(50 ms post excitation) emissions at 620 nM (native europiumfluorescence) and 665 nm (europium fluorescence transferred toallophycocyanin—an index of substrate phosphorylation) was determined(Park et al, 1999).Data Analysis: The proportion of substrate phosphorylated in the kinasereaction in the presence of compound compared with that phosphorylatedin the presence of DMSO vehicle alone (HI control) was calculated usingthe formula: % control (POC)=(compound−average LO)/(average HI−averageLO)*100. Data (consisting of POC and inhibitor concentration in μM) wasfitted to a 4-parameter equation (y=A+((B−A)/(1+((x/C)̂D))), where A isthe minimum y (POC) value, B is the maximum y (POC), C is the x(compound concentration) at the point of inflection and D is the slopefactor, using a Levenburg-Marquardt non-linear regression algorithm.

The inhibition constant (Ki) of the inhibitor was estimated from theIC₅₀ (compound concentration at the point of inflection C) using theCheng-Prussof equation: Ki=IC₅₀/(1+S/Km), where S is the ATP substrateconcentration, and Km is the Michaelis constant for ATP as determinedexperimentally. All results were expressed as the mean±the standarderror of the mean. Data acquisition and non-linear regression algorithmswere performed using Activity Base v5.2 and XL-fit software v4.1respectively. All data was archived using Activity Base v5.2 software.Data for Exemplary compounds in the human p38-alpha enzyme assay isprovided in Table 1. Examples 1-3 and 5-29 exhibited IC₅₀ values of lessthan or equal to 100 nM.

Lipopolysaccharide-Activated Pbmc Cytokine Production Assay Isolation ofPBMC

Test compounds were evaluated in vitro for the ability to inhibit theproduction of IL-1β, IL-6, and TNF-α by PBMC activated with bacteriallipopolysaccharide (LPS). Fresh leukocytes were obtained from a localblood bank, and peripheral blood mononuclear cells (PBMCs) were isolatedby density gradient centrifugation on Ficol-Paque Plus (Pharmacia).

Preparation of Test Compound Stock Solutions

All reagents were prepared in RPMI 1640+10% v/v human AB serum+1×Pens/Strep/Glu (assay medium). Test compounds were dissolved in 100%DMSO and serially diluted in 96-well polypropylene round bottom microtiter plates (drug plate). Serial dilutions were then diluted 1:250 intoassay medium to a 4× working concentration. Compound serial dilutionswere half-log, 10 point titrations with a final starting concentrationof 1 μM.

Treatment of Cells with Test Compounds and Activation withLipopolysaccharide

LPS was prepared to a 4× concentration in assay medium. 100 μl of PBMC(1×10⁶ cells/ml) were plated in a 96-well polystyrene flat bottom microtiter tissue culture plate and incubated with 50 μl of 4× compoundserial dilution for 1 hour at 37° C., 5% CO₂ in a tissue cultureincubator. 50 μl 4×LPS or control was added and the plates wereincubated at 37° C., 5% CO₂ in a tissue culture incubator for 18 hours.The final DMSO concentration was 0.1%. The total volume was 200 μL. Thefinal LPS concentration was 100 ng/mL. After 18 hours culturesupernatants were removed and IL-1β, IL-6, and TNF-α presence in thesupernatants was quantified using MSD ECL based technology.

Cytokine Measurements

20 μL of culture supernatant were added to MSD plates, and incubated forone hour at room temperature. 20 μL of detection antibody diluted inantibody diluent (1 μg/mL), and 110 μL of 2× Read Buffer P was added,and incubated for one hour at RT. Electrochemiluminescence was measuredusing the SECTOR HTS Imager (MSD, Gaithersburg, Md.).

Data Analysis

Compound IC₅₀ values were calculated as follows: The proportion ofcytokine production in the presence of compound compared to the cytokineproduction in the presence of the DMSO vehicle alone (Hi control) wascalculated using the formula: Percent Control (POC)=(compound−averageLo)/(average Hi−average Lo)*100. To derive IC₅₀ values, POC was plottedagainst the Log of compound concentration (μM) and fitted to a4-parameter equation (y=A+((B−A)/(1+((x/C)̂D))), where A is the minimum y(POC) value, B is the maximum y (POC), C is the concentration ofcompound at the inflection point, and D is the slope factor, using aLevenburg-Marquardt non-linear regression algorithm. Data acquisitionand non-linear regression were performed using Activity Base and XL-fitrespectively. The compounds of Examples 1-3, 5-25 and 29 exhibitedactivities in the whole blood PMBC assay with IC₅₀ values of equal to1000 nM or less. A majority of these examples exhibited IC₅₀ values ofequal to 150 nM or less.

Compounds of the invention can also be shown to inhibit LPS-inducedrelease of IL-1β, IL-6 and/or IL-8 from PBMC by measuring concentrationsof IL-1β, IL-6 and/or IL-8 by methods well known to those skilled in theart. In a similar manner to the above described assay involving the LPSinduced release of TNF-α from PBMC, compounds of this invention can alsobe shown to inhibit LPS induced release of IL-1β, IL-6 and/or IL-8 fromPBMC by measuring concentrations of IL-1β, IL-6 and/or IL-8 by methodswell known to those skilled in the art. Thus, the compounds of theinvention may lower elevated levels of TNF-α, IL-1, IL-6, and IL-8levels. Reducing elevated levels of these inflammatory cytokines tobasal levels or below is favorable in controlling, slowing progression,and alleviating many disease states. All of the compounds are useful inthe methods of treating disease states in which TNF-α, IL-1β, IL-6, andIL-8 play a role to the full extent of the definition of TNF-α-mediateddiseases described herein.

Lipopolysaccharide-Activated THP1 Cell TNF Production Assay

THP1 cells were resuspended in fresh THP1 media (RPMI 1640, 10%heat-inactivated FBS, 1×PGS, 1×NEAA, plus 30 μM βME) at a concentrationof 1.5×10⁶ cells per mL. One hundred microliters of cells per well wereplated in a polystyrene 96-well tissue culture plate. 1.5 micrograms permL of bacterial LPS was prepared in THP1 media and transferred to thefirst 11 columns of a 96-well polypropylene plate. Column 12 containedonly THP1 media for the LO control. Compounds were dissolved in 100%DMSO and serially diluted 3 fold in a polypropylene 96-well microtiterplate (drug plate). Columns 6 and 12 were reserved as controls (HIcontrols and LO controls respectively) and contained only DMSO. 10 μL ofLPS followed by one microliter of inhibitor compound from the drug platewas transferred to the cell plate. The treated cells were induced tosynthesize and secrete TNF-α in a 37° C. humidified incubator with 5%CO₂ for 3 hours. Fifty microliters of conditioned media was transferredto a 96-well MULTI-ARRAY™ 96-well small spot plate—custom coated withMAB610 containing 100 μL of 2× Read Buffer P supplemented with 0.34 nMAF210NA polyclonal Ab labeled with ruthenium (MSD—Sulfo-TAG™—NHS ester).After an overnight incubation at room temperature with shaking, thereaction was read on the Sector Imager™ 6000. A low voltage was appliedto the ruthenylated TNF-α immune complexes, which in the presence of TPA(the active component in the ECL reaction buffer, Read Buffer P),resulted in a cyclical redox reaction generating light at 620 nm. Theamount of secreted TNF-α in the presence of test compounds compared withthat in the presence of DMSO vehicle alone (HI control) was calculatedusing the formula: % control (POC)=(cpd−average LO)/(averageHI−averageLO)*100. Data (consisting of POC and inhibitor concentrationin μM) was fitted to a 4-parameter equation (y=A+((B−A)/(1+((x/C)̂D))),where A is the minimum y (POC) value, B is the maximum y (POC), C is thex (cpd concentration) at the point of inflection and D is the slopefactor) using a Levenburg-Marquardt non-linear regression algorithm. Thecompounds of Examples 1-3, 5-25 and 29 exhibited activities in the THP-1cellular TNF production assay with IC₅₀ values of 1000 nM or less. Amajority of these exemplary compounds exhibited IC₅₀ values of 250 nM orless.

Inhibition of TNF-α Induced IL-8 in 50% Human Whole Blood

Test compounds were evaluated in vitro for the ability to inhibit theproduction of secreted IL-8 by whole blood activated with TNF-α. Freshhuman whole blood was obtained from healthy, non-medicated volunteers insodium heparin tubes.

Compound Dilution—Assay Procedure

Test compounds are serially diluted 1:3 in DMSO and then diluted 1:250into R10 (RPMI 1640, 10% human serum AB, 1× pen/strep/glutamine) to the4× working concentration to be used in the assay. 100 ul heparinizedwhole blood is plated into wells of 96 well flat bottom plates. 50 ul ofeither 4× compound or DMSO control (Final DMSO concentration is 0.1%)are added to the appropriate wells. Plates are incubated for 1 hour at37 degrees Celsius. 50 ul of 4×TNF-α (4 nM TNF-α, for a finalconcentration of 1 nM) or control (media alone) is added to theappropriate wells (Total volume=200 ul). Plates are incubated overnight(16-18 hours). 100 ul of supernatant is collected and stored in 96-wellround bottom polypropylene plates at −80 degrees Celsius or assayedimmediately for IL-8.

Cytokine Measurement

Cytokines are measured on antibody (Ab) sandwich ECL based 96-welldetection plates. 20 ul of supernatant are added to plate and plate issealed and shaken at RT for 1 hour. 130 ul of detection Ab cocktail isadded and plates are sealed and shaken for 1 hour in the dark at RT.Plates are read on MSD Sector HTS instrument. Data are analyzed and IC₅₀values generated using Activity Base and X1-fit programs. Data forexemplary compounds in the TNF-α Induced IL-8 in 50% Human Whole Bloodassay is provided in Tables 1. Examples 1-3, 5-14, 16, 17, 19, 21-23, 25and 29 exhibited IC₅₀ values of less than or equal to 100 nM.

Inhibition of LPS-Induced TNF-α Production Rats

LPS was diluted in PBS (100 μg per rat). Rats (n=6) were pretreated withvehicle or compound (0.03, 0.1, 0.3 and 1.0 mg/kg, PO) 60 minutes priorto the injection of LPS (100 μg per rat/IV, tail vein). Blood washarvested via decapitation 90 minutes following the administration ofLPS. Blood was centrifuged at 12,000 rpm for 12 minutes to obtainplasma. Plasma samples were stored at −80 C. TNF-α levels weredetermined by ELISA for treatment groups that received LPS. Rat TNF-αlevels were analyzed using rat TNF-α CytoSet kit from BiosourceInternational. ELISA was completed according to the manufacturer'sinstructions. The concentration of TNF-α was interpolated fromabsorbance using the standard curve generated. For each individualsample, the TNF value from the dilution series that fell in the mostlinear portion of the standard curve was chosen and used for dataanalysis. The limit of quantitation of the ELISA was 1,000 pg/mL. TheCompounds of examples 1, 3 and 14 exhibited an ED₅₀ of 0.06, 0.04 and0.02 mg/kg, respectively.

Compounds of the invention may be shown to have anti-inflammatoryproperties in animal models of inflammation, including carageenan pawedema, collagen induced arthritis and adjuvant arthritis, such as thecarageenan paw edema model (C. A. Winter et al., Proc. Soc. Exp. Biol.Med., 111:544 (1962); K. F. Swingle, in R. A. Scherrer and M. W.Whitehouse, Eds., Anti-inflammatory Agents, Chemistry and Pharmacology,13(II):33, Academic, New York (1974) and collagen induced arthritis (D.E. Trentham et al., J. Exp. Med., 146:857 (1977); J. S. Courtenay,Nature (New Biol.), 283:666 (1980)).

Collagen-induced Arthritis (CIA) Model in Rats

Porcine type II collagen (10 mg) was dissolved in 0.1N acetic acid (5mL) two days prior to use on a rotating plate in the refrigerator.Subsequently, collagen was emulsified 1:1 with Freund's incompleteadjuvant using an emulsification needle and glass syringes yielding afinal concentration of 1 mg/mL.

Disease was induced in each animal by intradermal injection ofemulsified collagen in IFA at 10 different sites (100 μL per site) overthe back. The clinical onset of arthritis varied between days 10 to 12as indicated by hind paw swelling and ambulatory difficulties. At onset(defined as Day 0), rats were randomized to treatment groups and therapywas initiated with drug or vehicle control as noted in table above. Ratswere treated for 7 days and were sacrificed on Day 8. Paw swelling andother measurements of efficacy is described Schett et al (Schett et al.Arthritis and Rheum. 52:1604 (2005). The compound examples may be shownto exhibit potency in the rat CIA model. For example, compound examples1 and 14 both exhibited an ED₅₀ of 0.03 mg/kg.

Cyclooxygenase Enzyme Activity Assay

The human monocytic leukemia cell line, THP-1, differentiated byexposure to phorbol esters expresses only COX-1; the human osteosarcomacell line 143B expresses predominantly COX-2. THP-1 cells are routinelycultured in RPMI complete media supplemented with 10% FBS and humanosteosarcoma cells (HOSC) are cultured in minimal essential mediasupplemented with 10% fetal bovine serum (MEM-10% FBS); all cellincubations are at 37° C. in a humidified environment containing 5% CO₂.

COX-1 Assay

In preparation for the COX-1 assay, THP-1 cells are grown to confluency,split 1:3 into RPMI containing 2% FBS and 10 mM phorbol 12-myristate13-acetate (TPA), and incubated for 48 h on a shaker to preventattachment. Cells are pelleted and resuspended in Hank's Buffered Saline(HBS) at a concentration of 2.5×10⁶ cells/mL and plated in 96-wellculture plates at a density of 5×10⁵ cells/mL. Test compounds arediluted in HBS and added to the desired final concentration and thecells are incubated for an additional 4 hours. Arachidonic acid is addedto a final concentration of 30 mM, the cells incubated for 20 minutes at37° C., and enzyme activity determined as described below.

COX-2 Assay

For the COX-2 assay, subconfluent HOSC are trypsinized and resuspendedat 3×10⁶ cells/mL in MEM-FBS containing 1 ng human IL-1b/mL, plated in96-well tissue culture plates at a density of 3×10⁴ cells per well,incubated on a shaker for 1 hour to evenly distribute cells, followed byan additional 2 hour static incubation to allow attachment. The media isthen replaced with MEM containing 2% FBS (MEM-2% FBS) and 1 ng humanIL-1b/mL, and the cells incubated for 18-22 h. Following replacement ofmedia with 190 mL MEM, 10 mL of test compound diluted in HBS is added toachieve the desired concentration and the cells incubated for 4 h. Thesupernatants are removed and replaced with MEM containing 30 mMarachidonic acid, the cells incubated for 20 minutes at 37° C., andenzyme activity determined as described below.

COX Activity Determined

After incubation with arachidonic acid, the reactions are stopped by theaddition of 1N HCl, followed by neutralization with 1 N NaOH andcentrifugation to pellet cell debris. Cyclooxygenase enzyme activity inboth HOSC and THP-1 cell supernatants is determined by measuring theconcentration of PGE₂ using a commercially available ELISA (Neogen#404110). A standard curve of PGE₂ is used for calibration, andcommercially available COX-1 and COX-2 inhibitors are included asstandard controls. Various compounds of the invention may be shown toinhibit the COX-1 and/or COX-2 activity.

Indications

Accordingly, compounds of the invention are useful for, but not limitedto, the prevention or treatment of inflammation, pro-inflammatorycytokines levels including, without limitation, TNF, IL-1, IL-2, IL-6and/or IL-8, and disease associated therewith. The compounds of theinvention have p38 kinase modulatory activity. In one embodiment of theinvention, there is provided a method of treating a disorder related tothe activity of p38 enzyme in a subject, the method comprisingadministering to the subject an effective dosage amount of a compound ofa compound of Formulas I, I-A, I-B or I-C, or Formula II.

Accordingly, the compounds of the invention would be useful in therapyas anti-inflammatory agents in treating inflammation, or to minimizedeleterious effects of p38. Based on the ability to modulatepro-inflammatory cytokine production, the compounds of the invention arealso useful in treatment and therapy of cytokine-mediated diseases.Particularly, these compounds can be used for the treatment ofrheumatoid arthritis, Pagets disease, osteoporosis, multiple myeloma,uveitis, acute or chronic myelogenous leukemia, pancreatic β celldestruction, osteoarthritis, rheumatoid spondylitis, gouty arthritis,inflammatory bowel disease, adult respiratory distress syndrome (ARDS),psoriasis, Crohn's disease, allergic rhinitis, ulcerative colitis,anaphylaxis, contact dermatitis, asthma, muscle degeneration, cachexia,Reiter's syndrome, type I diabetes, type II diabetes, bone resorptiondiseases, graft vs. host reaction, Alzheimer's disease, stroke,myocardial infarction, ischemia reperfusion injury, atherosclerosis,brain trauma, multiple sclerosis, cerebral malaria, sepsis, septicshock, toxic shock syndrome, fever, myalgias due to HIV-1, HIV-2, HIV-3,cytomegalovirus (CMV), influenza, adenovirus, the herpes viruses orherpes zoster infection, or any combination thereof, in a subject.

An example of an inflammation related disorder is (a) synovialinflammation, for example, synovitis, including any of the particularforms of synovitis, in particular bursal synovitis and purulentsynovitis, as far as it is not crystal-induced. Such synovialinflammation may for example, be consequential to or associated withdisease, e.g. arthritis, e.g. osteoarthritis, rheumatoid arthritis orarthritis deformans. The present invention is further applicable to thesystemic treatment of inflammation, e.g. inflammatory diseases orconditions, of the joints or locomotor apparatus in the region of thetendon insertions and tendon sheaths. Such inflammation may be, forexample, consequential to or associated with disease or further (in abroader sense of the invention) with surgical intervention, including,in particular conditions such as insertion endopathy, myofascialesyndrome and tendomyosis. The present invention is further applicable tothe treatment of inflammation, e.g. inflammatory disease or condition,of connective tissues including dermatomyositis and myositis.

The compounds of the invention can also be used as active agents againstsuch disease states as arthritis, atherosclerosis, psoriasis, psoriaticpain, atopic dermatitis hemoangiomas, myocardial angiogenesis, coronaryand cerebral collaterals, ischemic limb angiogenesis, wound healing,peptic ulcer Helicobacter related diseases, fractures, cat scratchfever, rubeosis, neovascular glaucoma and retinopathies such as thoseassociated with diabetic retinopathy or macular degeneration.

The compounds of the invention are also useful in the treatment ofdiabetic conditions such as diabetic retinopathy and microangiopathy.

The compounds of the present invention are also useful for treatingankylosing spondylitis, inflammatory bowel disease, inflammatory pain,ulcerative colitis, Crohn's disease, asthma, chronic obstructivepulmonary disease, myelodysplastic syndrome, endotoxic shock, chronichepatitis C or a combination thereof.

Thus, the present invention provides methods for the treatment of p38protein kinase-associated disorders, comprising the step ofadministering to a subject, including human subjects, prophylacticallyor therapeutically, at least one compound of the Formula I or of FormulaII in an amount effective therefore. Other therapeutic agents such asthose described below may be employed with the inventive compounds inthe present methods. In the methods of the present invention, such othertherapeutic agent(s) may be administered prior to, simultaneously withor following the administration of the compound(s) of the presentinvention. The present invention also provides for a method for treatingatopic dermatitis by administration of a therapeutically effectiveamount of a compound of the present invention to a patient, whether ornot in need of such treatment.

In yet another embodiment, the compounds are useful for decreasing thelevel of, or lowering plasma concentrations of one or more of TNF-α,IL-1β, IL-6 and IL-8 in a subject, including human subjects, generally amammal and typically a human.

In yet another embodiment, the compounds are useful for treating a paindisorder, such as inflammatory pain, psoriatic pain, arthritic pain andthe like in a subject, including human subjects, by administering to thesubject an effective dosage amount of a compound according to formulasI, I-A, I-B or I-C or Formula II.

In yet another embodiment, the compounds are useful for treatingdiabetes in a subject, including human subjects, by administering to thesubject an effective dosage amount of a compound according to formulasI, I-A, I-B or I-C or Formula II, to produce a glucagon antagonisteffect.

In yet another embodiment, the compounds are useful for decreasingprostaglandin production in a subject, including human subjects, byadministering to the subject an effective dosage amount of a compoundaccording to formulas I, I-A, I-B or I-C or Formula II.

In yet another embodiment, the compounds are useful for decreasingcyclooxygenase enzyme activity in a subject, including human subjects,by administering to the subject an effective amount of a compoundaccording to formulas I, I-A, I-B or I-C or Formula II.

In yet another embodiment, the cyclooxygenase enzyme is COX-2.

Besides being useful for human treatment, these compounds are useful forveterinary treatment of companion animals, exotic animals and farmanimals, including mammals, rodents, and the like. For example, animalsincluding horses, dogs, and cats may be treated with compounds providedby the invention.

Formulations and Method of Use

Treatment of diseases and disorders herein is intended to also includetherapeutic administration of a compound of the invention, apharmaceutical salt thereof, or a pharmaceutical composition of eitherto a subject (i.e., an animal, preferably a mammal, most preferably ahuman) which may be in need of preventative treatment, such as, forexample, for pain, inflammation and the like. Treatment also encompassesprophylactic administration of a compound of the invention, apharmaceutical salt thereof, or a pharmaceutical composition of eitherto a subject (i.e., an animal, preferably a mammal, most preferably ahuman). Generally, the subject is initially diagnosed by a licensedphysician and/or authorized medical practitioner, and a regimen forprophylactic and/or therapeutic treatment via administration of thecompound(s) or compositions of the invention is suggested, recommendedor prescribed.

The amount of compound(s) which is/are administered and the dosageregimen for treating TNF-α, IL-1, IL-6, and IL-8 mediated diseases,cancer, and/or hyperglycemia with the compounds and/or compositions ofthis invention depends on a variety of factors, including the age,weight, sex and medical condition of the subject, the type of disease,the severity of the disease, the route and frequency of administration,and the particular compound employed. Thus, the dosage regimen may varywidely, but can be determined routinely using standard methods. A dailydose of about 0.001 mg/kg to 500 mg/kg, advantageously between about0.005 and about 50 mg/kg, more advantageously about 0.005 and about 30mg/kg, even more advantageously between about 0.005 and about 10 mg/kg,and even more advantageously about 0.01 and about 5 mg/kg, and should beuseful for all methods of use disclosed herein. The daily dose can beadministered in one to four doses per day.

While it may be possible to administer a compound alone, the compound ofFormulas I, I-A, I-B or I-C or Formula II is normally administered as anactive pharmaceutical ingredient (API) in a composition comprising othersuitable and pharmaceutically acceptable excipients. This admixture istypically referred to as a pharmaceutical composition. This compositionshould be pharmaceutically acceptable. In another embodiment, theinvention provides a pharmaceutical composition comprising a compound ofthe present invention in combination with a pharmaceutically acceptableexcipient. Pharmaceutical excipients generally include diluents,carriers, adjuvants and the like (collectively referred to herein as“excipient” materials) as described herein, and, if desired, otheractive ingredients.

A pharmaceutical composition of the invention may comprise an effectiveamount of a compound of the invention or an effective dosage amount of acompound of the invention. An effective amount of the compound istypically that amount capable of bring about a desired physiologicaleffect in the subject. An effective dosage amount of a compound of theinvention includes an amount less than, equal to or greater than aneffective amount of the compound; for example, a pharmaceuticalcomposition in which two or more unit dosages, such as in tablets,capsules and the like, are required to administer an effective amount ofthe compound, or alternatively, a multidose pharmaceutical composition,such as powders, liquids and the like, in which an effective amount ofthe compound is administered by administering a portion of thecomposition. Alternatively, a pharmaceutical composition in which two ormore unit dosages, such as in tablets, capsules and the like, arerequired to administer an effective amount of the compound may beadministered in less than an effective amount for one or more periods oftime, for example to ascertain the effective dose for an individualsubject, to desensitize an individual subject to potential side effects,to permit effective dosing readjustment or depletion of one or moreother therapeutics administered to an individual subject, and/or thelike.

The compound(s) of the present invention may be administered by anysuitable route, preferably in the form of a pharmaceutical compositionadapted to such a route, and in a dose effective for the treatmentintended. The compounds and compositions of the present invention may,for example, be administered orally, mucosally, topically, rectally,pulmonarily such as by inhalation spray, or parentally includingintravascularly, intravenously, intraperitoneally, subcutaneously,intramuscularly intrasternally and infusion techniques, in dosage unitformulations containing conventional pharmaceutically acceptablecarriers, adjuvants, and vehicles.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are tablets or capsules. For example, these maycontain an amount of API from about 1 to 2000 mg, advantageously fromabout 1 to 500 mg, and typically from about 5 to 150 mg. A suitabledaily dose for a human or other mammal may vary widely depending on thecondition of the patient and other factors, but, once again, can bedetermined using routine methods and practices.

For therapeutic purposes, the compounds of this invention are ordinarilycombined with one or more adjuvants or “excipients” appropriate to theindicated route of administration. If orally administered on a per dosebasis, the compounds may be admixed with lactose, sucrose, starchpowder, cellulose esters of alkanoic acids, cellulose alkyl esters,talc, stearic acid, magnesium stearate, magnesium oxide, sodium andcalcium salts of phosphoric and sulfuric acids, gelatin, acacia gum,sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, to formthe final formulation. For example, the compound(s) and excipient(s) maybe tableted or encapsulated by known and accepted methods for convenientadministration. Examples of suitable formulations include, withoutlimitation, pills, tablets, soft and hard-shell gel capsules, troches,orally-dissolvable forms and delayed or controlled-release formulationsthereof. Particularly, capsule or tablet formulations may contain one ormore controlled-release agents, such as hydroxypropylmethyl cellulose,as a dispersion with the active compound(s).

In the case of psoriasis and other skin conditions, it may be preferableto apply a topical preparation of compounds of this invention to theaffected area two to four times a day. Formulations suitable for topicaladministration include liquid or semi-liquid preparations suitable forpenetration through the skin (e.g., liniments, lotions, ointments,creams, pastes, suspensions and the like) and drops suitable foradministration to the eye, ear, or nose. A suitable topical dose ofactive ingredient of a compound of the invention is 0.1 mg to 150 mgadministered one to four, preferably one or two times daily. For topicaladministration, the active ingredient may comprise from 0.001% to 10%w/w, e.g., from 1% to 2% by weight of the formulation, although it maycomprise as much as 10% w/w, but preferably not more than 5% w/w, andmore preferably from 0.1% to 1% of the formulation.

When formulated in an ointment, the active ingredients may be employedwith either paraffinic or a water-miscible ointment base. Alternatively,the APIs may be formulated in a cream with an oil-in-water cream base.If desired, the aqueous phase of the cream base may include, for exampleat least 30% w/w of a polyhydric alcohol such as propylene glycol,butane-1,3-diol, mannitol, sorbitol, glycerol, polyethylene glycol andmixtures thereof. The topical formulation may desirably include acompound, which enhances absorption or penetration of the activeingredient through the skin or other affected areas. Examples of suchdermal penetration enhancers include DMSO and related analogs.

The compounds of this invention can also be administered by transdermaldevice. Preferably transdermal administration will be accomplished usinga patch either of the reservoir and porous membrane type or of a solidmatrix variety. In either case, the active agent is deliveredcontinuously from the reservoir or microcapsules through a membrane intothe active agent permeable adhesive, which is in contact with the skinor mucosa of the recipient. If the active agent is absorbed through theskin, a controlled and predetermined flow of the active agent isadministered to the recipient. In the case of microcapsules, theencapsulating agent may also function as the membrane.

The oily phase of the emulsions of this invention may be constitutedfrom known ingredients in a known manner. While the phase may comprisemerely an emulsifier, it may comprise a mixture of at least oneemulsifier with a fat or an oil or with both a fat and an oil.Preferably, a hydrophilic emulsifier is included together with alipophilic emulsifier, which acts as a stabilizer. It is also preferredto include both an oil and a fat. Together, the emulsifier(s) with orwithout stabilizer(s) make-up the so-called emulsifying wax, and the waxtogether with the oil and fat make up the so-called emulsifying ointmentbase, which forms the oily dispersed phase of the cream formulations.Emulsifiers and emulsion stabilizers suitable for use in the formulationof the present invention include, for example, Tween 60, Span 80,cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, sodiumlauryl sulfate, glyceryl distearate alone or with a wax, or othermaterials well known in the art.

The choice of suitable oils or fats for the formulation is based onachieving the desired cosmetic properties, since the solubility of theactive compound in most oils likely to be used in pharmaceuticalemulsion formulations is very low. Thus, the cream should preferably bea non-greasy, non-staining and washable product with suitableconsistency to avoid leakage from tubes or other containers. Straight orbranched chain, mono- or dibasic alkyl esters such as di-isoadipate,isocetyl stearate, propylene glycol diester of coconut fatty acids,isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters may be used.These may be used alone or in combination depending on the propertiesrequired. Alternatively, high melting point lipids such as white softparaffin and/or liquid paraffin or other mineral oils can be used.

Formulations for parenteral administration may be in the form of aqueousor non-aqueous isotonic sterile injection solutions or suspensions.These solutions and suspensions may be prepared from sterile powders orgranules using one or more of the carriers or diluents mentioned for usein the formulations for oral administration or by using other suitabledispersing or wetting agents and suspending agents. The compounds may bedissolved in water, polyethylene glycol, propylene glycol, ethanol, cornoil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodiumchloride, tragacanth gum, and/or various buffers. Other adjuvants andmodes of administration are well and widely known in the pharmaceuticalart. The active ingredient may also be administered by injection as acomposition with suitable carriers including saline, dextrose, or water,or with cyclodextrin (ie. Captisol), cosolvent solubilization (ie.propylene glycol) or micellar solubilization (ie. Tween 80).

The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution, and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employed,including synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The API may also be administered by injection as a composition withsuitable carriers including saline, dextrose, or water. The dailyparenteral dosage regimen will be from about 0.1 to about 30 mg/kg oftotal body weight, preferably from about 0.1 to about 10 mg/kg, and morepreferably from about 0.25 mg to 1 mg/kg.

For pulmonary administration, the pharmaceutical composition may beadministered in the form of an aerosol or with an inhaler including drypowder aerosol.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable non-irritating excipient such as cocoabutter and polyethylene glycols that are solid at ordinary temperaturesbut liquid at the rectal temperature and will therefore melt in therectum and release the drug.

The pharmaceutical compositions may be subjected to conventionalpharmaceutical operations such as sterilization and/or may containconventional adjuvants, such as preservatives, stabilizers, wettingagents, emulsifiers, buffers etc. Tablets and pills can additionally beprepared with enteric coatings. Such compositions may also compriseadjuvants, such as wetting, sweetening, flavoring, and perfuming agents.

Accordingly, in yet another embodiment, the present invention providesthe use of a medicament for the treatment of inflammatory conditions,including RA, psoriasis, psoriatic arthritis, pain, COPD, Crohn'sdisease, and other indications described herein.

In yet another embodiment, there is provided a method of manufacturing amedicament for the treatment of inflammation, the method comprisingcombining an amount of a compound according to Formulas I, I-A, I-B orI-C or Formula II with a pharmaceutically acceptable carrier tomanufacture the medicament.

Combinations

While the compounds of the invention can be dosed or administered as thesole active pharmaceutical agent, they can also be used in combinationwith one or more compounds of the invention or in conjunction with otheragents. When administered as a combination, the therapeutic agents canbe formulated as separate compositions that are administeredsimultaneously or sequentially at different times, or the therapeuticagents can be given as a single composition.

The phrase “co-therapy” (or “combination-therapy”), in defining use of acompound of the present invention and another pharmaceutical agent, isintended to embrace administration of each agent in a sequential mannerin a regimen that will provide beneficial effects of the drugcombination, and is intended as well to embrace co-administration ofthese agents in a substantially simultaneous manner, such as in a singlecapsule having a fixed ratio of these active agents or in multiple,separate capsules for each agent.

Specifically, the administration of compounds of the present inventionmay be in conjunction with additional therapies known to those skilledin the art in the prevention or treatment of TNF-α, IL-1, IL-6, and IL-8mediated diseases, cancer, and/or hyperglycemia.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the accepted dosage ranges. Compoundsof Formulas I, I-B or I-C or Formula II may also be administeredsequentially with known anti-inflammatory agents when a combinationformulation is inappropriate. The invention is not limited in thesequence of administration; compounds of the invention may beadministered either prior to, simultaneous with or after administrationof the known anti-inflammatory agent.

The compounds of the invention may also be used in co-therapies withanti-neoplastic agents such as other kinase inhibitors, including CDKinhibitors, TNF inhibitors, metallomatrix proteases inhibitors (MMP),COX-2 inhibitors including celecoxib, rofecoxib, parecoxib, valdecoxib,and etoricoxib, NSAID's, SOD mimics or α_(v)β₃ inhibitors.

The foregoing description is merely illustrative of the invention and isnot intended to limit the invention to the disclosed compounds,compositions and methods. Variations and changes, which are obvious toone skilled in the art, are intended to be within the scope and natureof the invention, as defined in the appended claims. From the foregoingdescription, one skilled in the art can easily ascertain the essentialcharacteristics of this invention, and without departing from the spiritand scope thereof, can make various changes and modifications of theinvention to adapt it to various usages and conditions. All patents andother publications recited herein are hereby incorporated by referencein their entireties.

1. A compound of Formula I:

or a stereoisomer or pharmaceutically acceptable salt thereof, wherein Ais CR⁵ or N; R¹ is C₁₋₈-alkyl, —OC₁₋₈-alkyl, —SC₁₋₈-alkyl,—NHC₁₋₈-alkyl, —N(C₁₋₈-alkyl)₂, C₂₋₈-alkenyl, C₂₋₈-alkynyl orC₃₋₈-cycloalkyl, each of which is optionally substituted with 1-5substituents of R⁹, or R¹ is a 3-8 membered monocyclic or 6-12 memberedbicyclic ring system, said ring system formed of carbon atoms optionallyincluding 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic,said heteroatoms selected from O, N, or S, wherein said ring system isoptionally substituted independently with 1-5 substituents of R⁹; eachof R² and R³, independently, is H, halo, haloalkyl, NO₂, CN, C₁₋₆-alkyl,C₁₋₆-alkoxyl, C₁₋₆-thioalkyl, C₁₋₆-aminoalkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl or C₃₋₆-cycloalkyl, each of the C₁₋₆-alkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl and C₃₋₁₀-cycloalkyl optionally substituted with 1-5substituents of R⁹; R⁴ is CN, C(O)R⁹, C₁₋₆-alkyl, —OC₁₋₆-alkyl,C₂₋₆-alkenyl, C₂₋₆-alkynyl or C₃₋₆-cycloalkyl, each of the C₁₋₆-alkyl,—OC₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₁₀-alkynyl and C₃₋₆-cycloalkyl optionallysubstituted with 1-5 substituents of R⁹; each R⁵, independently, is H,halo, haloalkyl, NO₂, CN, OH, C₁₋₆-alkyl, —OC₁₋₆-alkyl, —SC₁₋₆-alkyl,—NHC₁₋₆-alkyl, wherein the C₁₋₆-alkyl of each is optionally comprising1-3 heteroatoms selected from N, O and S and optionally substituted with1-5 substituents of R⁹; R⁶ is C(O)NR⁷R⁷, C(O)NR⁷R⁸, NR⁷C(O)R⁷,NR⁷C(O)R⁸, NR⁷C(O)NR⁷R⁷, NR⁷C(O)NR⁷R⁸, S(O)₂NR⁷R⁷, S(O)₂NR⁷R⁸,NR⁷S(O)₂NR⁷R⁸, NR⁷S(O)₂R⁷ or NR⁷S(O)₂R⁸; each R⁷, independently, is H,C₁₋₈-alkyl, C₂₋₈-alkenyl, C₂₋₈-alkynyl or C₃₋₈-cycloalkyl, each of theC₁₋₈-alkyl, C₂₋₈-alkenyl, C₂₋₈-alkynyl and C₃-cycloalkyl optionallycomprising 1-4 heteroatoms selected from N, O and S and optionallysubstituted with one or more substituents of NR⁸R⁹, NR⁹R⁹, OR⁸, SR⁸,OR⁹, SR⁹, C(O)R⁸, OC(O)R⁸, COOR⁸, C(O)R⁹, OC(O)R⁹, COOR⁹, C(O)NR⁸R⁹,C(O)NR⁹R⁹, NR⁹C(O)R⁸, NR⁹C(O)R⁹, NR⁹C(O)NR⁸R⁹, NR⁹C(O)NR⁹R⁹, NR⁹(COOR⁸),NR⁹(COOR⁹), OC(O)NR⁸R⁹, OC(O)NR⁹R⁹, S(O)₂R⁸, S(O)₂NR⁸R⁹, S(O)₂R⁹,S(O)₂NR⁹R⁹, NR⁹S(O)₂NR⁸R⁹, NR⁹S(O)₂NR⁹R⁹, NR⁹S(O)₂R⁸, NR⁹S(O)₂R⁹, R⁸ orR⁹; R⁸ is a partially or fully saturated or fully unsaturated 3-8membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclicring system, said ring system formed of carbon atoms optionallyincluding 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S,and wherein each ring of said ring system is optionally substitutedindependently with 1-5 substituents of R⁹, oxo, NR⁹R⁹, OR⁹, SR⁹, C(O)R⁹,COOR⁹, C(O)NR⁹R⁹, NR⁹C(O)R⁹, NR⁹C(O)NR⁹R⁹, OC(O)NR⁹R⁹, S(O)₂R⁹,S(O)₂NR⁹R⁹, NR⁹S(O)₂R⁹, or a partially or fully saturated or unsaturated5-6 membered ring of carbon atoms optionally including 1-3 heteroatomsselected from O, N, or S, and optionally substituted independently with1-3 substituents of R⁹; alternatively, R⁷ and R⁸ taken together form asaturated or partially or fully unsaturated 5-6 membered monocyclic or7-10 membered bicyclic ring of carbon atoms optionally including 1-3heteroatoms selected from O, N, or S, and the ring optionallysubstituted independently with 1-5 substituents of R⁹; R⁹ is H, halo,haloalkyl, CN, OH, NO₂, NH₂, acetyl, oxo, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl, —SO₂C₁₋₁₀-alkylor a saturated or partially or fully unsaturated 5-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S,wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and each ring ofsaid ring system is optionally substituted independently with 1-3substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl; X is O or S; and n is 0, 1 or
 2. 2.The compound of claim 1, or a pharmaceutically acceptable salt thereof,wherein each R⁵, independently, is H, F, Cl, Br, CF₃, —OCF₃, C₂F₅,—OC₂F₅, —O—C₁₋₄-alkyl, —C₁₋₄-alkyl-O—C₁₋₄-alkyl, —S—C₁₋₄-alkyl,—C₁₋₄-alkyl-S—C₁₋₄-alkyl, —NH—C₁₋₄-alkyl, —N(C₁₋₄-alkyl)₂,—C₁₋₄-alkyl-NH—C₁₋₄-alkyl, —C₁₋₃-alkyl-N(C₁₋₄-alkyl)₂, NO₂, NH₂, CN orC₁₋₈-alkyl, the C₁₋₈-alkyl optionally substituted with 1-5 substituentsof R⁹.
 3. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R¹ is C₁₋₈-alkyl, —OC₁₋₈-alkyl, —SC₁₋₈-alkyl,—NHC₁₋₈-alkyl, —N(C₁₋₈-alkyl)₂, C₂₋₈-alkenyl, C₂₋₈-alkynyl orC₃₋₈-cycloalkyl, each of which is optionally substituted with 1-5substituents of R⁹.
 4. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R¹ is phenyl, pyridyl, pyrimidyl,triazinyl, pyridazinyl, pyrazinyl, thiophenyl, furyl, tetrahydrofuryl,pyrrolyl, tetrahydropyrrolyl, pyrazolyl, imidazolyl, triazolyl,tetrazolyl, thiazolyl, oxazolyl, oxazolinyl, isoxazolyl, isoxazolinyl,oxadiazolyl, isothiazolyl, morpholinyl, piperidinyl, piperazinyl,pyranyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each ofwhich is optionally substituted with 1-5 substituents of R⁹.
 5. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein each of R² and R³, independently, is H.
 6. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein R⁴ is CN,C(O)R⁹, —OC₁₋₆-alkyl, C₁₋₄-alkylC(O)R⁹, methyl, ethyl, propyl,isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentylor C₁₋₄-alkyl-amino-C₁₋₄-alkyl or C₁₋₁₀-dialkylaminoC₁₋₄-alkyl-.
 7. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R⁶ is C(O)NR⁷R⁷, C(O)NR⁷R⁸, NR⁷C(O)R⁷, NR⁷C(O)R⁸, S(O)₂NR⁷R⁷,S(O)₂NR⁷R⁸, NR⁷S(O)₂R⁷ or NR⁷S(O)₂R⁸.
 8. The compound of claim 7, or apharmaceutically acceptable salt thereof, wherein R⁸ is a ring selectedfrom phenyl, naphthyl, pyridyl, pyrimidyl, triazinyl, pyridazinyl,pyrazinyl, quinolinyl, isoquinolinyl, quinazolinyl, isoquinazolinyl,thiophenyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl,thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl, isoindolyl,benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl,benzisoxazolyl, benzopyrazolyl, benzothiazolyl, tetrahydrofuranyl,pyrrolidinyl, oxazolinyl, isoxazolinyl, thiazolinyl, pyrazolinyl,morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, wherein said ringis optionally substituted independently with 1-3 substituents of R⁹. 9.The compound of claim 1, or a pharmaceutically acceptable salt thereof,wherein A is CH or N; R¹ is phenyl, pyridyl, pyrimidyl, triazinyl,pyridazinyl, pyrazinyl, thiophenyl, furyl, tetrahydrofuryl, pyrrolyl,tetrahydropyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl,thiazolyl, oxazolyl, oxazolinyl, isoxazolyl, isoxazolinyl, oxadiazolyl,isothiazolyl, morpholinyl, piperidinyl, piperazinyl, pyranyl,cyclopropyl, cyclobutyl, cyclopentyl or cyclorhexyl, each of which isoptionally substituted with 1-5 substituents of R⁹; each of R² and R³,independently, is H, halo, haloalkyl or C₁₋₄-alkyl; R⁴ is CN, C(O)R⁷,—OC₁₋₆-alkyl, C₁₋₄-alkylC(O)R⁷, methyl, ethyl, propyl, isopropyl,cyclopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl orC₁₋₄-alkyl-amino-C₁₋₄-alkyl or C₁₋₁₀-dialkylaminoC₁₋₄-alkyl-; each R⁵,independently, is H, F, Cl, Br, CF₃, —OCF₃, C₂F₅, —OC₂F₅, —O—C₁₋₆-alkyl,—C₁₋₄-alkyl-O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl, —C₁₋₄-alkyl-S—C₁₋₆-alkyl,—NH—C₁₋₆-alkyl, —N(C₁₋₆-alkyl)₂, —C₁₋₄-alkyl-NH—C₁₋₆-alkyl,—C₁₋₃-alkyl-N(C₁₋₄-alkyl)₂, NO₂, NH₂, CN or C₁₋₆-alkyl, the C₁₋₆-alkyloptionally substituted with one or more substituents of R⁹; R⁶ isC(O)NR⁷R⁷, C(O)NR⁷R⁸, NR⁷C(O)R⁷, NR⁷C(O)R⁸, S(O)₂NR⁷R⁷, S(O)₂NR⁷R⁸,NR⁷S(O)₂R⁷ or NR⁷S(O)₂R⁸; each R⁷, independently, is H, C₁₋₁₀-alkyl orC₃₋₁₀-cycloalkyl, wherein the C₁₋₁₀-alkyl and C₃₋₁₀-cycloalkyloptionally comprising 1-4 heteroatoms selected from N, O and S andoptionally substituted with 1-3 substituents of R⁹; R⁸ is a ringselected from phenyl, naphthyl, pyridyl, pyrimidyl, triazinyl,pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, quinazolinyl,isoquinazolinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl, imidazolyl,triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl,isoindolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl,benzisoxazolyl, benzopyrazolyl, benzothiazolyl, tetrahydrofuranyl,pyrrolidinyl, oxazolinyl, isoxazolinyl, thiazolinyl, pyrazolinyl,morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, wherein said ringis optionally substituted independently with 1-3 substituents of R⁹; andR⁹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, oxo, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl,C₁₋₁₀-thioalkoxyl, —SO₂C₁₋₁₀-alkyl or a saturated or partially or fullyunsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14membered tricyclic ring system, said ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms ifbicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selectedfrom O, N, or S, wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and each ring ofsaid ring system is optionally substituted independently with 1-3substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl; X is O; and n is 0 or
 1. 10. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein A is CH; R¹ is C₁₋₆-alkyl, —OC₁₋₆-alkyl, —SC₁₋₆-alkyl,—NHC₁₋₆-alkyl or a ring selected from phenyl, pyridyl, pyrimidyl,pyridazinyl, pyrazinyl, thiophenyl, furyl, tetrahydrofuryl, pyrrolyl,tetrahydropyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl,oxazolyl, isoxazolyl, isothiazolyl, morpholinyl, piperidinyl,piperazinyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclorhexyl, eachof C₁₋₆-alkyl, —OC₁₋₆-alkyl, —SC₁₋₆-alkyl, —NHC₁₋₆-alkyl and ringoptionally substituted with 1-5 substituents of R⁹; each of R² and R³,independently, is H, F, Cl, CF₃, methyl or ethyl; R⁴ is CN, C(O)R⁷,—OC₁₋₆-alkyl, C₁₋₄-alkylC(O)R⁷, methyl, ethyl, propyl, isopropyl,cyclopropyl, butyl, isobutyl, tert-butyl, pentyl,C₁₋₄-alkyl-amino-C₁₋₄-alkyl or C₁₋₄-dialkylaminoC₁₋₄-alkyl-; each R⁵,independently, is H, F, Cl, Br, CF₃, —OCF₃, C₂F₅, —OC₂F₅, OH, —O-methyl,—S-methyl, —NH-methyl, —N(methyl)₂, NO₂, NH₂, CN or C₁₋₁₀-alkyl, theC₁₋₁₀-alkyl optionally substituted with one or more substituents of R⁷;R⁶ is C(O)NR⁷R⁷, C(O)NR⁷R⁸, NR⁷C(O)R⁷ or NR⁷C(O)R⁸; each R⁷,independently, is H, C₁₋₆-alkyl or C₃₋₆-cycloalkyl, wherein theC₁₋₆-alkyl and C₃₋₆-cycloalkyl optionally comprising 1-3 heteroatomsselected from N, O and S and optionally substituted with 1-3substituents of R⁹; R⁸ is a ring selected from phenyl, naphthyl,pyridyl, pyrimidyl, triazinyl, pyridazinyl, pyrazinyl, thiophenyl,furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl,thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, tetrahydrofuranyl,pyrrolidinyl, oxazolinyl, isoxazolinyl, thiazolinyl, pyrazolinyl,morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, wherein said ringis optionally substituted independently with 1-3 substituents of R⁹; R⁹is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, oxo, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl,C₁₋₁₀-thioalkoxyl, —SO₂C₁₋₁₀-alkyl or a saturated or partially or fullyunsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14membered tricyclic ring system, said ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms ifbicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selectedfrom O, N, or S, wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and each ring ofsaid ring system is optionally substituted independently with 1-3substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl; X is O; and n is 0 or
 1. 11. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,selected from:N-cyclopropyl-3-(8-(2,4-difluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazin-3-yl)-4-methylbenzamide;3-(8-(2,4-difluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazin-3-yl)-4-methylbenzamide;N-cyclopropyl-3-(8-(2,4-difluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazin-3-yl)-5-fluoro-4-methylbenzamide;4-chloro-N-cyclopropyl-3-(8-(2,4-difluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazin-3-yl)benzamide;N-cyclopropyl-4-methyl-3-(1-methyl-2-oxo-8-o-tolyl-1,2-dihydropyrido[3,2-d]pyridazin-3-yl)benzamide;N-cyclopropyl-3-fluoro-4-methyl-5-(1-methyl-2-oxo-8-o-tolyl-1,2-dihydropyrido[3,2-d]pyridazin-3-yl)benzamide;3-(8-(2-chlorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazin-3-yl)-N-cyclopropyl-4-methylbenzamide;N-cyclopropyl-3-(8-(2-fluoro-4-(trifluoromethyl)phenyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazin-3-yl)-4-methylbenzamide;N-cyclopropyl-4-methyl-3-(1-methyl-2-oxo-8-(2-(trifluoromethyl)phenyl)-1,2-dihydropyrido[3,2-d]pyridazin-3-yl)benzamide;N-cyclopropyl-3-fluoro-4-methyl-5-(1-methyl-2-oxo-8-(2-(trifluoromethyl)phenyl)-1,2-dihydropyrido[3,2-d]pyridazin-3-yl)benzamide;N-cyclopropyl-3-(8-(4-fluoro-2-methylphenyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazin-3-yl)-4-methylbenzamide;3-(8-(2-chloro-4-fluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-N-cyclopropyl-4-methylbenzamide;3-(8-(2-chlorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-N-cyclopropyl-5-fluoro-4-methylbenzamide;3-(8-(2,4-difluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-4-methyl-N-(1-methyl-1H-pyrazol-5-yl)benzamide;N-cyclopropyl-3-fluoro-5-(8-(4-fluoro-2-methylphenyl)-1-methyl-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-4-methylbenzamide;3-(8-(2-chloro-4-fluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-N-cyclopropyl-5-fluoro-4-methylbenzamide;3-(8-(2-chloro-5-fluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-N-cyclopropyl-4-methylbenzamide;3-(8-(2-chloro-5-fluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-N-cyclopropyl-5-fluoro-4-methylbenzamide;3-(8-(2-chloro-4-fluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-4-methyl-N-(1-methylcyclopropyl)benzamide;3-(8-(2-chloro-4-fluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-N-3-isoxazolyl-4-methylbenzamide;N-cyclopropyl-3-(8-(2,4-difluorophenyl)-1-ethyl-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-5-fluoro-4-methylbenzamide;N-cyclopropyl-3-(8-(2,4-difluorophenyl)-1-ethyl-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-4-methylbenzamide;3-(8-(2-chloro-4-fluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-4-methyl-N-1,3-thiazol-2-ylbenzamide;3-(8-(2-chlorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-N-3-isoxazolyl-4-methylbenzamide;N-cyclopropyl-4-methyl-3-(1-methyl-8-(2-methyl-4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)benzamide;N-cyclopropyl-3-fluoro-4-methyl-5-(1-methyl-8-(2-methyl-4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)benzamide;3-(8-(2-chlorophenyl)-1-ethyl-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-N-cyclopropyl-4-methylbenzamide;N-cyclopropyl-4-(8-(2,4-difluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-5-methyl-2-pyridinecarboxamide;3-(8-(2,4-difluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)—N,4-dimethylbenzamide;3-(8-(2,4-difluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-4-methyl-N-1,3-thiazol-2-ylbenzamide;and3-(8-(2,4-difluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-N-3-isoxazolyl-4-methylbenzamide.12. A compound of Formula I-A:

or a pharmaceutically acceptable salt thereof, wherein R¹ is C₁₋₆-alkyl,—OC₁₋₆-alkyl, —SC₁₋₆-alkyl, —NHC₁₋₆-alkyl or a ring selected fromphenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, thiophenyl, furyl,tetrahydrofuryl, pyrrolyl, tetrahydropyrrolyl, pyrazolyl, imidazolyl,triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, morpholinyl,piperidinyl, piperazinyl, cyclopropyl, cyclobutyl, cyclopentyl orcyclorhexyl, each of C₁₋₆-alkyl, —OC₁₋₆-alkyl, —SC₁₋₆-alkyl,—NHC₁₋₆-alkyl and ring optionally substituted with 1-5 substituents ofR⁹; each of R² and R³, independently, is H or halo; R⁴ is CN, C(O)R⁷,C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl or C₃₋₈-cycloalkyl, each of theC₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl and C₃₋₈-cycloalkyl optionallycomprising 1-4 heteroatoms selected from N, O and S and optionallysubstituted with one or more substituents of R⁹; each R⁵, independently,is H, halo, haloalkyl, NO₂, CN, OR⁷, NR⁷R⁷ or C₁₋₆-alkyl; R⁶ isC(O)NR⁷R⁷ or C(O)NR⁷R⁸; each R⁷, independently, is H, C₁₋₆-alkyl orC₃₋₆-cycloalkyl, each of the C₁₋₆-alkyl, and C₃₋₆-cycloalkyl optionallysubstituted with one or more substituents of R⁹; R⁸ is a ring selectedfrom phenyl, naphthyl, pyridyl, pyrimidyl, triazinyl, pyridazinyl,pyrazinyl, quinolinyl, isoquinolinyl, quinazolinyl, isoquinazolinyl,thiophenyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl,thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl, isoindolyl,benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl,benzisoxazolyl, benzopyrazolyl, benzothiazolyl, tetrahydrofuranyl,pyrrolidinyl, oxazolinyl, isoxazolinyl, thiazolinyl, pyrazolinyl,morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, wherein said ringis optionally substituted independently with 1-3 substituents of R⁹; andR⁹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, oxo, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl,C₁₋₁₀-thioalkoxyl, —SO₂C₁₋₁₀-alkyl or a saturated or partially or fullyunsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14membered tricyclic ring system, said ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms ifbicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selectedfrom O, N, or S, wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and each ring ofsaid ring system is optionally substituted independently with 1-3substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl.
 13. The compound of claim 12, or apharmaceutically acceptable salt thereof, wherein R¹ is phenyl, pyridyl,pyrimidyl, triazinyl, pyridazinyl, pyrazinyl, thiophenyl, furyl,tetrahydrofuryl, pyrrolyl, tetrahydropyrrolyl, pyrazolyl, imidazolyl,triazolyl, tetrazolyl, thiazolyl, oxazolyl, oxazolinyl, isoxazolyl,isoxazolinyl, oxadiazolyl, isothiazolyl, morpholinyl, piperidinyl,piperazinyl, pyranyl, cyclopropyl, cyclobutyl, cyclopentyl orcyclorhexyl, each of which is optionally substituted with 1-5substituents of R⁹; each of R² and R³, independently, is H, F or Cl; R⁴is CN, C(O)CH₃, C₁₋₄-alkylC(O)R⁷, methyl, ethyl, propyl, isopropyl orC₁₋₄-alkyl-amino-C₁₋₄-alkyl or C₁₋₁₀-dialkylaminoC₁₋₄-alkyl-; each R⁵,independently, is H, CH₃, C₂H₅, F, Cl, Br, CF₃, —OCF₃, C₂F₅, —OC₂F₅,—OCH₃, —SCH₃ or —NHCH₃; R⁶ is C(O)NR⁷R⁸; R⁷ is H or CH₃; R⁸ is a ringselected from phenyl, naphthyl, pyridyl, pyrimidyl, triazinyl,pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, quinazolinyl,isoquinazolinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl, imidazolyl,triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl,isoindolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl,benzisoxazolyl, benzopyrazolyl, benzothiazolyl, tetrahydrofuranyl,pyrrolidinyl, oxazolinyl, isoxazolinyl, thiazolinyl, pyrazolinyl,morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, wherein said ringis optionally substituted independently with 1-3 substituents of R⁹; andR⁹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, oxo, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl,C₁₋₁₀-thioalkoxyl, —SO₂C₁₋₁₀-alkyl or a saturated or partially or fullyunsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14membered tricyclic ring system, said ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms ifbicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selectedfrom O, N, or S, wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and each ring ofsaid ring system is optionally substituted independently with 1-3substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl.
 14. A pharmaceutical compositioncomprising a compound according to claim 11 and a pharmaceuticallyacceptable excipient.
 15. A method of treating rheumatoid arthritis in asubject, the method comprising administering to the subject an effectivedosage amount of a compound of claim
 11. 16. A method of treatingrheumatoid arthritis in a subject, the method comprising administeringto the subject the pharmaceutical composition of claim
 14. 17. A methodof treating Pagets disease, osteoporosis, multiple myeloma, uveitis,acute or chronic myelogenous leukemia, pancreatic β cell destruction,osteoarthritis, rheumatoid spondylitis, gouty arthritis, adultrespiratory distress syndrome (ARDS), Crohn's disease, allergicrhinitis, dental pain, anaphylaxis, contact dermatitis, asthma, muscledegeneration, cachexia, Reiter's syndrome, type I diabetes, type IIdiabetes, bone resorption diseases, graft vs. host reaction, Alzheimer'sdisease, stroke, myocardial infarction, ischemia reperfusion injury,atherosclerosis, brain trauma, multiple sclerosis, cerebral malaria,sepsis, septic shock, toxic shock syndrome, fever, myalgias due toHIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), influenza, adenovirus, theherpes viruses or herpes zoster infection or a combination thereof in asubject, the method comprising administering to the subject an effectivedosage amount of a compound of claim
 11. 18. A method of lowering plasmaconcentrations of TNF-a, IL-1, IL-6, IL-8 or a combination thereof in asubject, the method comprising administering to the subject an effectivedosage amount of a compound of claim
 11. 19. A method of treatingpsoriasis, psoriatic arthritis, atopic dermatitis or a combinationthereof in a subject, the method comprising administering to the subjectan effective dosage amount of a compound of claim
 11. 20. A method oftreating ankylosing spondylitis, inflammatory bowel disease (IBD),inflammatory pain, ulcerative colitis, Crohn's disease, asthma, chronicobstructive pulmonary disease (COPD), myelodisplastic syndrome,interpulmonary cystic fibrosis (IPF), endotoxic shock or a combinationthereof in a subject, the method comprising administering to the subjectan effective dosage amount of a compound of claim
 11. 21. A method ofpreparing a compound according to claim 1, the method comprising thestep of reacting a compound 7

wherein R¹, R², R³, R⁴ and X are as defined in claim 1 and Y is ahalogen, with a boronic acid having a general formula

wherein R⁵ and R⁶ are as defined in claim 1, to make the compound ofclaim 1.